sign in sign up
<<
Home , Diproqualone, Lapisteride

THETWO TONTTITUNTIVIUS 20180264013A1 DA TI ON AND MAIN ( 19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2018 /0264013 A1 DILL ( 43 ) Pub . Date : Sep . 20 , 2018 (54 ) COMPOSITION AND METHODS FOR Publication Classification TREATING SLEEP DISORDERS (51 ) Int. CI. A61K 31/ 60 (2006 . 01 ) ( 71 ) Applicant: WELLESLEY A61K 31 /4025 ( 2006 .01 ) PHARMACEUTICALS , LLC , A61K 45 / 06 ( 2006 .01 ) Newtown, PA (US ) A61K 31/ 616 ( 2006 . 01 ) A61K 31/ 4725 ( 2006 . 01 ) (72 ) Inventor : David A . DILL , Newtown , PA (US ) A61K 31 / 46 (2006 .01 ) A61K 31/ 405 ( 2006 .01 ) A61K 9 / 00 ( 2006 .01 ) (21 ) Appl. No. : 15 /985 ,315 A61K 31 /216 ( 2006 . 01 ) A61K 31/ 192 (2006 . 01) ( 22 ) Filed : May 21 , 2018 A61K 31 / 19 ( 2006 .01 ) A61K 31/ 167 (2006 . 01) A61K 31 / 12 ( 2006 .01 ) Related U . S . Application Data (52 ) U . S . CI. @(63 ) Continuation - in -part of application No. 14 / 172, 649 , CPC ...... A61K 31 /60 (2013 . 01 ) ; A61K 31 /4025 filed on Feb . 4 , 2014 , which is a continuation of ( 2013 .01 ) ; A61K 45 / 06 ( 2013 .01 ) ; A61K application No . 13 / 847 , 927 , filed on Mar. 20 , 2013 , 31 /616 ( 2013 .01 ) ; A61K 31 /4725 ( 2013 .01 ) ; now Pat . No . 8 ,685 , 453 , which is a continuation of A61K 31/ 46 ( 2013 .01 ); A61K 2300 /00 application No. 13 / 560 ,607 , filed on Jul. 27 , 2012 , ( 2013 .01 ) ; A61K 9 /0002 ( 2013 . 01 ) ; A61K now Pat. No. 8 ,445 , 015 , which is a continuation of 31 /216 ( 2013 .01 ) ; A61K 31/ 192 ( 2013 .01 ) ; application No. 13/ 487, 348 , filed on Jun . 4 , 2012 , A61K 31/ 19 ( 2013 .01 ); A61K 31/ 167 now abandoned , which is a continuation - in -part of (2013 .01 ) ; A61K 31/ 12 ( 2013 .01 ) ; A61K application No . 13 /424 ,000 , filed on Mar. 19 , 2012 , 31/ 405 (2013 .01 ) now Pat. No. 8 , 236 ,857 , which is a continuation - in (57 ) ABSTRACT part of application No . 13 /343 , 332 , filed on Jan . 4 , A method for treating sleep disorders includes the step of 2012 , now abandoned , which is a continuation of administering to a subject in need therefor a pharmaceutical application No . 12 /956 ,634 , filed on Nov . 30 , 2010 , composition comprising one or more agents . Also now abandoned . disclosed is a pharmaceutical composition for treating sleep (60 ) Provisional application No . 61 / 362, 374 , filed on Jul. disorders. The pharmaceutical composition comprises one 8 , 2010 . or more analgesic agents and an anti- agent. Patent Application Publication Sep . 20 , 2018 US 2018 / 0264013 A1

00005.0 wenye 0005.0 005.0 LPSNSAID+ wawatu DoseofNSAID (5000-0.00005um) FIG.1B kamiliki Aspirin -ibuprofen Naproxen -0Acetaminophen www. * *

1 ww.

www.w 00005.0 www. 0005.0 Aspirin osmos(Ep45???* -0Acetaminophen -Naproxen com DoseofNSAID (5000-0.00005uM) FIG.1A NSAIDalone www

.

8 0 NSAID without control of Percent( cells + CD80 + CD40 US 2018 /0264013 A1 Sep . 20 , 2018

COMPOSITION AND METHODS FOR gesics, wherein each of the one or more is TREATING SLEEP DISORDERS administered in an amount of 5 mg to 2000 mg. [0008 ] Another aspect of the present application relates to [ 0001 ] This application is a continuation - in - part of U . S . a pharmaceutical composition for treating a sleep disorder, patent application Ser. No. 14 /172 ,649 , filed Feb . 4 , 2014 , comprising one or more analgesics , an anti - insomnia agent which is a continuation application of U . S . patent applica and a pharmaceutically acceptable carrier. In some embodi tion Ser . No. 13 /847 , 927 , filed on Mar . 20 , 2013 , now U . S . ments, the one or more analgesics comprise acetaminophen Pat . No . 8 ,685 ,453 , which is a continuation application of and ibuprofen , and the pharmaceutical composition is for U . S . patent application Ser . No. 13 / 560 ,607 , filed on Jul. 27 , 2012 , now U . S . Pat . No. 8 ,445 ,015 , which is a continuation mulated in the form of an orally disintegrating tablet application of U . S . patent application Ser. No . 13 /487 , 348 , filed Jun . 4 , 2012 , which is a continuation - in -part applica BRIEF DESCRIPTION OF DRAWINGS tion of U . S . patent application Ser . No . 13 / 424 , 000 , filed [0009 ] FIGS. 1A and 1B are diagrams showing that anal Mar. 19 . 2012 . now U . S . Pat. No . 8 , 236 ,857 , which is a gesics regulate expression of co - stimulatory molecules by continuation -in - part application of U . S . patent application Raw 264 macrophage cells in the absence (FIG . 1A ) or Ser. No . 13 / 343 , 332 , filed on Jan . 4 , 2012 , which is a presence (FIG . 1B ) of LPS . Cells were cultures for 24 hrs in continuation - in -part application of U . S . patent application the presence of analgesic alone or together with Salmonella Ser. No . 12 /956 ,634 , filed on Nov . 30 , 2010 , which claims typhimurium LPS (0 . 05 ug /ml ) . Results are mean relative % priority to 61/ 362 ,374 filed on Jul. 8 , 2010 . The entirety of of CD40 + CD80 + cells. the aforementioned applications are incorporated herein by reference . DETAILED DESCRIPTION [0010 ] The following detailed description is presented to FIELD enable any person skilled in the art to make and use the invention . For purposes of explanation , specific nomencla [0002 ] The present application generally relates to meth ture is set forth to provide a thorough understanding of the ods and compositions for the treatment of sleep disorders . present invention . However , it will be apparent to one skilled in the art that these specific details are not required to BACKGROUND practice the invention . Descriptions of specific applications 0003 ] Sleep disorders , such as insomnia , are common are provided only as representative examples. The present sleep problems that affect hundreds of millions of people . invention is not intended to be limited to the embodiments People with insomnia usually experience one or more of the shown, but is to be accorded the broadest possible scope following symptoms: fatigue, low energy , difficulty concen consistent with the principles and features disclosed herein . trating , mood disturbances , depression , and decreased per formance in work or at school. Method for Treating Sleep Disorders [0004 ] Medical literature has recognized four types of [0011 ] One aspect of the present application relates to a insomnia , including sleep onset insomnia ( e. g. , trouble fall method for treating sleep disorders or otherwise improving ing asleep at bedtime) , sleep maintenance insomnia ( e. g ., quality of sleep . The method comprises the step of admin disturbed sleep during the night ), early morning awakening , istering to a person in need thereof an effective amount of a and transient insomnia ( e . g . , new environment, first night in pharmaceutical composition comprising one or more anal hotel syndrome) . Other types of insomnia include “ middle gesic agents . In some embodiments , the pharmaceutical of - the - night” insomnia , “ late night” insomnia , “ prolonged composition further comprises one or more active agents awakening after sleep onset ” insomnia , “ sleep maintenance " selected from the group consisting of anti - insomnia agents , insomnia , and insomnia that follows after “ middle -of - the antimuscarinic agents , antidiuretic agents , spasmolytics , night” awakening , each of which has a component of a - blockers , 5a - reductase inhibitors , phosphodiesterase type interrupted sleep . 5 ( PDE5 ) inhibitors and prostaglandin (PD ) pathway inhibi [ 0005 ] Currently available treatments for insomnia have tors In some embodiments , the sleeping disorder is insom side effects and their effectiveness may decrease over time. nia . In some embodiments , the pharmaceutical composition Accordingly , there exists a continued need for new drug comprises acetaminophen and ibuprofen . compositions and methods for treating insomnia . [0012 ] The pharmaceutical composition may be adminis tered via systemic administration or topical administration . SUMMARY Systemic administration includes oral administration and parenteral ( including subcutaneous (subQ or SC ) , intramus [0006 ] One aspect of the present application relates to a cular ( IM ) , intraperitoneal ( IP ) , intravenous ( IV ) , intrathe method for treating a sleep disorder , comprising: adminis cal, intraventricular, etc . ) administration . Topical adminis tering to a subject in need thereof an effective amount of a tration includes administration to dermal and mucosal pharmaceutical composition comprising one or more anal tissues , such as transdermal administration , nasal adminis gesics, wherein the one or more analgesics are formulated in tration , buccal administration , and pulmonary administra an immediate - release formulation or a controlled - release tion . In some embodiments , the pharmaceutical composition formulation . In some embodiments , the sleep disorder is is administered by orally administration . In other embodi insomnia . ments , the pharmaceutical composition is administered by [0007 ] Another aspect of the present application relates to transdermal administration . a method for treating insomnia , comprising: administering [0013 ] As used herein , the term “ sleep disorder” refers to to a subject in need thereof an effective amount of a problems with the quality , timing and amount of sleep , pharmaceutical composition comprising one or more anal which cause problems with functioning and distress during US 2018 /0264013 A1 Sep . 20 , 2018 the daytime . There is a variety of different types of sleep , , , , butobar disorders, of which insomnia is the most common . Other bital, mephobarbital, , , and vinyl sleep disorders include narcolepsy , obstructive sleep apnea bital; and derivatives such as , and restless leg syndrome. diproqualone, (Aolan , Athinazone, Ethinazone ), [0014 ] As used herein , the term “ insomnia ” refers to the , (Nubarene , Casfen ), and difficulty falling asleep or staying asleep , even when a ( Quaalude ) ; such as clora person has the chance to do so . Medical literature has zepate, , , , , lora recognized four types of insomnia , including sleep onset zepam , , , , , insomnia ( e .g ., trouble falling asleep at bedtime) , sleep , , , , maintenance insomnia ( e. g ., disturbed sleep during the , , , , , night) , early morning awakening , and transient insomnia ; non -benzodiazepines , such as and ( e . g . , new environment , first night in hotel syndrome) . Other ; such as and types of insomnia include “middle -of - the- night ” insomnia , ; ; such as trazodonee , “ late night” insomnia , “ prolonged awakening after sleep , , , and mir onset" insomnia , “ sleep maintenance ” insomnia , and insom tazapine ; such as , clozapine , nia that follows after “ middle -of - the -night ” awakening, each , , , zotepine , , of which has a component of interrupted sleep . Insomnia guanfacine , , tetrahydrocannabinol, , may also be characterized as acute insomnia or chronic , , , imagabalin . insomnia based on its duration . Acute insomnia is brief and [ 0019 ] As used herein , the term “ antimuscarinic agent” often happens because of life circumstances ( for example , refers to agents, compounds or drugs that inhibit the bio when you can ' t fall asleep the night before an exam , or after logical activity of muscarinic receptor. Examples of the receiving stressful or bad news) . Chronic insomnia is dis antimuscarinic agents include, but are not limited to , oxy rupted sleep that occurs at least three nights per week and butynin , solifenacin , darifenacin , fesoterodine , tolterodine , lasts at least three months . trospium and atropine . [0015 ] As used herein , the term “ analgesic ” or “ analgesic [0020 ] As used herein , the term “ antidiuretic agent” refers agent” refers to agents , compounds or drugs used to relieve to agents , compounds or drugs that help to control fluid pain and inclusive of anti - inflammatory compounds . Exem balance in a human body by reducing urination . In some plary analgesic and /or anti - inflammatory agents , compounds embodiments , the antidiuretic agent ( s ) act to : ( 1 ) increase or drugs include, but are not limited to , the following vasopressin secretion ; ( 2 ) increase vasopressin receptor acti substances : non -steroidal anti - inflammatory drugs vation ; ( 3 ) reduce secretion of atrial natriuretic peptide (NSAIDs ) , salicylates , aspirin , , methyl salicy (ANP ) or C - type natriuretic peptide (CNP ) ; or ( 4 ) reduce late , diflunisal, salsalate , olsalazine , sulfasalazine , para ANP and / or CNP receptor activation . Exemplary antidi aminophenol derivatives , acetanilide , acetaminophen , phen uretic agents include , but are not limited to , antidiuretic acetin , fenamates , , meclofenamate , sodium hormone ( ADH ) , angiotensin II , aldosterone , vasopressin , meclofenamate , heteroaryl acetic acid derivatives , tolmetin , vasopressin analogs ( e . g ., desmopressin argipressin , lypres ketorolac , diclofenac , propionic acid derivatives , ibuprofen , sin , felypressin , ornipressin , terlipressin ) ; vasopressin recep naproxen sodium , naproxen , fenoprofen , ketoprofen , flurbi tor agonists , atrial natriuretic peptide ( ANP ) and C - type profen , oxaprozin ; enolic acids , oxicam derivatives, piroxi natriuretic peptide (CNP ) receptor ( i . e ., NPR1, NPR2 , cam , meloxicam , tenoxicam , ampiroxicam , droxicam , piv NPR3) antagonists ( e . g ., HS- 142 - 1 , isatin , [ Asu7 , 23 ' ] b oxicam , pyrazolon derivatives , phenylbutazone , ANP - 07 - 28 )] , anantin , a cyclic peptide from Streptomyces oxyphenbutazone , antipyrine , aminopyrine, dipyrone, coerulescens, and 3G12 monoclonal antibody) ; somatostatin coxibs , celecoxib , rofecoxib , nabumetone , apazone, indo type 2 receptor antagonists ( e . g ., somatostatin ) , and phar methacin , sulindac , etodolac , isobutylphenyl propionic acid , maceutically - acceptable derivatives , analogs, salts , lumiracoxib , etoricoxib , parecoxib , valdecoxib , tiracoxib , hydrates, and solvates thereof. etodolac , darbufelone , dexketoprofen , aceclofenac , [0021 ] As used herein , the term “ spasmolytics” refers to licofelone , bromfenac , loxoprofen , pranoprofen , piroxicam , agents , compounds or drugs that suppress muscle spasms. nimesulide, cizolirine, 3 - formylamino - 7 -methylsulfo Examples of the antimuscarinic agents include, but are not nylamino - 6 -phenoxy - 4H - 1 -benzopyran - 4 -one , meloxicam , limited to , cyclobenzaprine , , diazepam , lornoxicam , d - indobufen , mofezolac , amtolmetin , pranopro orphenadrine, , , , chlo fen , , flurbiprofen , suprofen , oxaprozin , zal rzoxazone , , dantrolene , baclofen , tizanidine and toprofen , alminoprofen , tiaprofenic acid , pharmacological dantrolene . salts thereof, hydrates thereof, and solvates thereof. [0022 ] As used herein , the term “ a - blockers” , also called [0016 ] As used herein , the terms “ coxib ” and “ COX " a - adrenergic -antagonists ” are pharmacological agents that inhibitor” refer to a composition of compounds that is act as receptor antagonists of a -adrenergic receptors , which capable of inhibiting the activity or expression of COX2 are further divided into al -adrenergic receptors and enzymes or is capable of inhibiting or reducing the severity , a2 - adrenergic receptors. Alpha blockers can be classified as including pain and swelling , of a severe inflammatory selective blockers that selectively act at al -adrenoceptors or response . a2 - adrenoceptors , and non - selective alpha blockers that act [ 0017 ] As used herein , the term “ effective amount” means at both types of a - adrenergic receptors . Examples of selec an amount necessary to achieve a selected result . tive al- adrenergic blockers include , but are not limited to , [0018 ] As used herein , the term “ anti - insomnia agent” , prazosin , , , , carve refers to agents , compounds or drugs used to treat insomnia . dilol, labetalol and . Examples of selective Exemplary anti - insomnia agents include , but are not limited a2 - adrenergic blockers include , but are not limited to , to , such as , , , atipamezole , idazoxane and yohimbine . Examples of non US 2018 /0264013 A1 Sep . 20 , 2018

selective a - adrenergic blockers include: phenoxyben cyclosporine, elacridar, fumitremorgin - C , gefitinib and zamine , phentolamine , tolazoline , , typical and erythromycin . Examples of PGT inhibitors that inhibit PGT atypical antipsychotics . expression include , but are not limited to , agents which [ 0023 ] As used herein , the term “ 5a - reductase inhibitor ” control the transcription of the MDR genes by targeting the refers to agents, compounds or drugs that inhibit the bio promoter region and / or transcription factors which bind to logical activity of 5a - reductase . Examples of 5a -reductase the promoter or other gene control regions . The term “ PGR inhibitors include , but are not limited to , , bex inhibitors, " as used herein , refers to agents that inhibit the losteride, , izonsteride, lapisteride, and turos activity or expression of PGRs . In some embodiments , the teride . PGRs comprise E prostanoid receptor EP1 , EP2 , EP3 , and [ 0024 ] As used herein , the term “ phosphodiesterase type 5 EP4 subtypes of the PGE receptor ; PGD receptor (DP1 ) ; (PDE5 ) inhibitor ” refers to agents , compounds or drugs that PGF receptor (FP ) ; PGI receptor ( IP ) ; and thromboxane inhibit the biological activity of PDE5 , such as tadalafil. receptor ( TP ) . Two additional isoforms of the human TP [0025 ] As used herein , the term " prostaglandin (PG )" ( TPa and TPB ) and FP ( FPA and FPB ) and eight EP3 refers to a group of lipid compounds that are derived variants are generated through alternative splicing , which enzymatically from fatty acids and have a variety of physi differ only in their C - terminal tails . In some embodiments , ological effects , such as regulating the contraction and the PGRs further comprise a G protein - coupled receptor relaxation of smooth muscle tissue, in the animal body . termed chemo- attractant receptor -homologous molecule Every prostaglandin contains 20 carbon atoms, including a (CRHIVIE ). In other embodiments, the PGRs include all of 5 - carbon ring. Examples of prostaglandin include , prosta the receptors that activate rhodopsin - like 7 - transmembrane glandin E1 (PGE ,) , prostaglandin E2 (PGE2 ) , Prostaglandin spanning G protein -coupled receptors . D2, prostaglandin 12 (PG12 , prostacyclin ), and prostaglandin [0030 ] Examples of PGR activity inhibitors include, but F2a ( PGF20 ) . are not limited to , anti -PGR antibodies and any agent that [0026 ] As used herein , the term “ prostaglandin (PG ) path inhibits the G - protein coupled receptor signaling pathway . way inhibitor” refers to agents that interact directly or PGR expression inhibitors include agents that inhibit PGR indirectly with one or more components involved in the expression at the transcriptional level , translational level or synthesis or action of PG on a target tissue , and interfere post transcriptional level . Examples of PGR expression with either the levels or the ultimate actions of prostaglandin inhibitors include , but are not limited to , anti - PGR siRNA on the target tissue . PG pathway inhibitors include, but are and mi RNAs. not limited to , PG inhibitors , prostaglandin transporter [ 0031 ] As used herein , the term " effective amount ” means ( PGT) inhibitors and prostaglandin receptor ( PGR ) inhibi an amount necessary to achieve a selected result . tors . The term " PG pathway inhibitor ," however, does not [0032 ] As used herein , the term “ analgesic ” refers to include the analgesics defined above . agents , compounds or drugs used to relieve pain and inclu [0027 ] The term “ PG inhibitors , " as used herein , include sive of anti- inflammatory compounds . Exemplary analgesic but are not limited to , inhibitors of PG synthesis and and /or anti - inflammatory agents , compounds or drugs inhibitors of PG activity . The term " inhibitors of PG syn include , but are not limited to , the following substances : thesis, " as used herein , refers to agents that inhibit the non - steroidal anti - inflammatory drugs (NSAIDs ) , salicy production of prostaglandin , such as agents that inhibit the lates, aspirin , salicylic acid , methyl salicylate , diflunisal, expression or activity of phospholipase A2, the prostaglan salsalate , olsalazine , sulfasalazine , para - aminophenol din synthases and the tissue specific isomerases and synthase derivatives , acetanilide , acetaminophen , phenacetin , fena enzymes such as: Thromboxane synthase , PGF synthase , mates , mefenamic acid , meclofenamate , sodium meclofena cytosolic PG synthase ( CPGES ) , prostaglandin I synthase mate , heteroaryl acetic acid derivatives, tolmetin , ketorolac , (PGIS ) and the microsomal PGES enzymes (mPGES ) . diclofenac , propionic acid derivatives, ibuprofen , naproxen Examples of PG synthesis inhibitors include flunixin meglu sodium , naproxen , fenoprofen , ketoprofen , flurbiprofen , mine . As used herein , the terms “ inhibitors of PG synthesis ” oxaprozin ; enolic acids , oxicam derivatives, piroxicam , and “ PG synthesis inhibitors" do not include the analgesics meloxicam , tenoxicam , ampiroxicam , droxicam , pivoxicam , defined below . pyrazolon derivatives , phenylbutazone , oxyphenbutazone, [0028 ] The term " inhibitors of PG activity ,” as used antipyrine, aminopyrine, dipyrone, coxibs , celecoxib , rofe herein , refers to agents that antagonize the action of pros coxib , nabumetone, apazone, indomethacin , sulindac , etod taglandin itself by any means . Agents that interfere solely olac, isobutylphenyl propionic acid , lumiracoxib , etoricoxib , with the synthesis of prostaglandins, such as by interfering parecoxib , valdecoxib , tiracoxib , etodolac , darbufelone , with the action of prostaglandin synthases , but which do not dexketoprofen , aceclofenac , licofelone , bromfenac, loxo interfere with the action of prostaglandins are not included profen , pranoprofen , piroxicam , nimesulide , cizolirine , within the definition of inhibitors of PG activity as used in 3 - formylamino - 7 - methylsulfonylamino - 6 - phenoxy -4H - 1 this specification . benzopyran - 4 - one, meloxicam , lornoxicam , d - indobufen , [0029 ] The term “ PGT inhibitors ," as used herein , refers to mofezolac , amtolmetin , pranoprofen , tolfenamic acid , flur agents that inhibit the expression or the activity of PG biprofen , suprofen , oxaprozin , zaltoprofen , alminoprofen , transporters , such as ATP dependent multi- drug resistance tiaprofenic acid , pharmacological salts thereof, hydrates (MDR ) transporter- 4 , or other MDR channels such as thereof, and solvates thereof. ABCC1, ABCC2 , ABCC3, ABCC6 , ABCG2 and ABCB11 . [ 0033 ] As used herein , the terms “ coxib ” and “ COX Examples of PGT inhibitors that inhibit PGT activity inhibitor ” refer to a composition of compounds that is include, but are not limited to , compounds that inhibit MDR capable of inhibiting the activity or expression of COX2 membrane pumps, such as triazine compounds, verapamil , enzymes or is capable of inhibiting or reducing the severity , and channel blockers ; channels include quinidines, including pain and swelling , of a severe inflammatory , itraconazole , azithromycin , valspodar, response . US 2018 /0264013 A1 Sep . 20 , 2018

[0034 ] In some embodiments , the pharmaceutical compo period of time, such as up to about 14 hours, about 13 hours , sition is formulated for immediate - release or controlled about 12 hours, about 11 hours, about 10 hours, about 9 release . In some embodiments , the pharmaceutical compo hours , about 8 hours , about 7 hours , about 6 hours , about 5 sition is formulated for delayed -release , extended - release , hours, about 4 hours , about 3 hours, about 2 hours , or about delayed - extended - release or combinations thereof. In some 1 hour following administration or following a lag period embodiments , the pharmaceutical composition is formulated associated with delayed -release of the drug . in the form of an orally disintegrating tablet. [0041 ] In certain preferred embodiments , the active agents [ 0035 ] As used hereinafter, the term “ immediate -release ” are released over a time interval of between about 2 to about refers to a drug formulation that does not contain a disso 14 hours . Alternatively , the active agents may be released lution rate controlling material. There is substantially no over about 3 , about 4 , about 5 , about 6 , about 7 , about 8 , delay in the release of the active agents following adminis about 9 , about 10 hours , about 11 hours, about 12 hours , tration of an immediate - release formulation . An immediate release coating may include suitable materials immediately about 13 hours or about 14 hours . In yet other embodiments , dissolving following administration so as to release the drug the active agents are released over a time period between contents therein . Exemplary immediate -release coating about 3 to about 12 hours or about 4 to about 8 hours materials include gelatin , polyvinyl polyethylene following administration . glycol (PVA -PEG ) copolymers ( e . g . ,) KOLLICOAT® and [0042 ] In some embodiments , the extended -release formu various other materials known to those skilled in the art . lation comprises an active core comprised of one or more [0036 In some embodiments , the pharmaceutical compo inert particles , each in the form of a bead , pellet, pill , sition of the present application is formulated for immediate granular particle ,microcapsule ,microsphere , microgranule , release . In some embodiments , the pharmaceutical compo nanocapsule , or nanosphere coated on its surfaces with sition of the present application has a combined -release drugs in the form of e . g ., a drug - containing coating or profile formulation that contains an immediate release com film - forming composition using , for example , fluid bed ponent. In some embodiments , the immediate release com techniques or other methodologies known to those of skill in ponent provides about 1 % to about 50 % of the total dosage the art . The inert particle can be of various sizes , so long as of the active agent( s ) to be delivered by the pharmaceutical it is large enough to remain poorly dissolved . Alternatively , composition . In some embodiments , the immediate - release the active core may be prepared by granulating and milling component may provide at least about 5 % , or about 10 % to and / or by extrusion and spheronization of a polymer com about 30 % , or about 45 % to about 50 % of the total dosage position containing the drug substance . of the active agent( s ) to be delivered by the formulation . In [ 0043 ] The active agents may be introduced to the inert some embodiments , the immediate -release component pro carrier by techniques known to one skilled in the art , such as vides about 2 , 4 , 5 , 10 , 15 , 20 , 25 , 30 , 35 , 40 , 45 , 50 , 55 , 60 , drug layering , powder coating , extrusion / spheronization , 65 or 70 % , of the total dosage of the active agent( s ) to be roller compaction or granulation . The amount of drug in the delivered by the formulation . core will depend on the dose that is required , and typically [0037 ] As used hereinafter , the term " controlled -release ” varies from about 5 to 90 % . Generally , the polymeric refers to a drug formulation that contains a dissolution rate coating on the active core will be from about 1 to 50 % based controlling material . Controlled -release formulations on the weight of the coated particle , depending on the lag include , but are not limited to , extended - release formulation , time required and /or the polymers and coating solvents delayed -release formulation , delayed -extended - release for chosen . Those skilled in the art will be able to select an mulation and combinations thereof. A controlled -release appropriate amount of drug for coating onto or incorporating formulation may include one or more immediate -release into the core to achieve the desired dosage . In one embodi components . ment, the inactive core may be a sugar sphere or a buffer [0038 ] Extended - release , also known as sustained -release crystal or an encapsulated buffer crystal such as calcium (SR ), sustained -action (SA ), time- release ( TR ), controlled carbonate , sodium bicarbonate , fumaric acid , tartaric acid , release (CR ) , modified release (MR ), or continuous- release etc . which alters the microenvironment of the drug to (CR ) , is a mechanism used in medicine tablets or capsules facilitate its release . to dissolve slowly and release the active ingredient over [0044 ] Extended -release formulations may utilize a vari time. The advantages of extended - release tablets or capsules ety of extended - release coatings or mechanisms facilitating are that they can often be taken less frequently than imme the gradual release of active agents over time. In some diate - release formulations of the same drug , and that they embodiments, the extended -release agent comprises a poly keep steadier levels of the drug in the bloodstream , thus mer controlling release by dissolution controlled release . In extending the duration of the drug action . a particular embodiment, the active agent( s) are incorpo [ 0039 ] In one embodiment, the pharmaceutical composi rated in a matrix comprising an insoluble polymer and drug tion is formulated for extended - release by embedding the particles or granules coated with polymeric materials of active ingredient in a matrix of insoluble substance ( s ) such varying thickness . The polymeric material may comprise a as acrylics or chitin . An extended - release form is designed lipid barrier comprising a waxy material , such as carnauba to release the active agent at a predetermined rate by wax , beeswax , spermaceti wax , candellila wax , shallac wax , maintaining a constant drug level for a specific period of cocoa butter , cetostearyl alcohol , partially hydrogenated time. This can be achieved through a variety of formulations, vegetable oils , ceresin , paraffin wax , ceresine , myristyl including , but not limited to liposomes and drug - polymer alcohol, stearyl alcohol, cetyl alcohol and stearic acid , along conjugates, such as hydrogels . with surfactants , such as polyoxyethylene sorbitan [0040 ] An extended - release formulation can be designed monooleate . When contacted with an aqueous medium , such to release the active agents at a predetermined rate so as to as biological fluids, the polymer coating emulsifies or erodes maintain a constant drug level for a specified , extended after a predetermined lag - time depending on the thickness of US 2018 /0264013 A1 Sep . 20 , 2018

the polymer coating . The lag time is independent of gastro molecular weight grades from Noveon , Inc ., Cincinnati, intestinal motility, pH , or gastric residence. Ohio ) ; carageenan ; polyvinyl acetate ( e . g . , KOLLIDON® [0045 ] In other embodiments , the extended - release agent SR ) ; polyvinyl pyrrolidone and its derivatives such as comprises a polymeric matrix effecting diffusion controlled crospovidone ; polyethylene oxides; and polyvinyl alcohol. release . The matrix may comprise one or more hydrophilic Preferred hydrophilic and water - swellable polymers include and / or water -swellable , matrix forming polymers, pH - de the cellulosic polymers , especially HPMC . pendent polymers, and /or pH -independent polymers. [0050 ] The extended -release formulation may further [0046 ] In one embodiment, the extended - release formula comprise at least one binder that is capable of cross- linking tion comprises a water soluble or water - swellable matrix the hydrophilic compound to form a hydrophilic polymer forming polymer, optionally containing one or more solu matrix ( i. e ., a gel matrix ) in an aqueous medium , including bility - enhancing excipients and /or release -promoting biological fluids. agents . Upon solubilization of the water- soluble polymer , [0051 ] Exemplary binders include homopolysaccharides, the active agent ( s ) dissolve ( if soluble ) and gradually diffuse such as galactomannan gums, guar gum , hydroxypropyl through the hydrated portion of the matrix . The gel layer guar gum , hydroxypropylcellulose (HPC ; e .g . , Klucel EXF ) grows with time as more water permeates into the core of the and locustbean gum . In other embodiments , the binder is an matrix , increasing the thickness of the gel layer and provid alginic acid derivative , HPC or microcrystallized cellulose ing a diffusion barrier to drug release . As the outer layer (MCC ). Other binders include , but are not limited to , becomes fully hydrated , the polymer chains become com starches, microcrystalline cellulose , hydroxypropyl cellu pletely relaxed and can no longer maintain the integrity of lose , hydroxyethyl cellulose , hydroxypropylmethyl cellu the gel layer, leading to disentanglement and erosion of the lose and polyvinylpyrrolidone . outer hydrated polymer on the surface of the matrix . Water [0052 ] In one embodiment, the introduction method is continues to penetrate towards the core through the gel layer , drug layering by spraying a suspension of active agent( s ) until it has been completely eroded . Whereas soluble drugs and a binder onto the inert carrier. are released by this combination of diffusion and erosion [0053 ] The binder may be present in the bead formulation mechanisms, erosion is the predominant mechanism for in an amount of from about 0 . 1 % to about 15 % by weight, insoluble drugs , regardless of dose . and preferably of from about 0 . 2 % to about 10 % by weight . [ 0047] Similarly , water- swellable polymers typically [ 0054 ] In some embodiments , the hydrophilic polymer hydrate and swell in biological fluids forming a homogenous matrix may further include an ionic polymer, a non -ionic matrix structure thatmaintains its shape during drug release polymer , or water- insoluble hydrophobic polymer to provide and serves as a carrier for the drug, solubility enhancers a stronger gel layer and / or reduce pore quantity and dimen and / or release promoters . The initial matrix polymer hydra sions in the matrix so as to slow diffusion and erosion rates tion phase results in slow - release of the drug ( lag phase ) . and concomitant release of the active agent( s ) . This may Once the water swellable polymer is fully hydrated and additionally suppress the initial burst effect and produce a swollen , water within the matrix can similarly dissolve the more steady " zero order release ” of active agent ( s ) . drug substance and allow for its diffusion out through the 10055 ] Exemplary ionic polymers for slowing dissolution matrix coating. rate include both anionic and cationic polymers. Exemplary [0048 ] Additionally, the porosity of the matrix can be anionic polymers include, for example , sodium carboxym increased due to the leaching out of pH - dependent release ethylcellulose (Na CMC ) , sodium alginate , polymers of promoters so as to release the drug at a faster rate . The rate acrylic acid or carbomers ( e . g . , CARBOPOL® 934 , 940 , of the drug release then becomes constant and is a function 974P NF) ; enteric polymers , such as polyvinyl acetate of drug diffusion through the hydrated polymer gel. The phthalate (PVAP ), methacrylic acid copolymers ( e . g . , release rate from the matrix is dependent upon various EUDRAGIT® L100 , L 30D 55 , A , and FS 30D ) , hypromel factors , including polymer type and level ; drug solubility lose acetate succinate ( AQUAT HPMCAS ) ; and xanthan and dose ; polymer : drug ratio ; filler type and level; polymer gum . Exemplary cationic polymers include , for example , to filler ratio ; particle size of drug and polymer ; and porosity dimethylaminoethyl methacrylate copolymer ( e . g . , and shape of the matrix . EUDRAGIT® E 100 ) . Incorporation of anionic polymers , [0049 ] Exemplary hydrophilic and /or water -swellable , particularly enteric polymers, is useful for developing a matrix forming polymers include, but are not limited to , pH - independent release profile for weakly basic drugs as cellulosic polymers, including hydroxyalkyl celluloses and compared to hydrophilic polymer alone . carboxyalkyl celluloses, such as hydroxypropylmethylcel [0056 ] Exemplary non - ionic polymers for slowing disso lulose (HPMC ), hydroxypropylcellulose (HPC ), hydroxy lution rate , include , for example , hydroxypropylcellulose ethylcellulose (HEC ) , methylcellulose (MC ) , carboxymeth (HPC ) and polyethylene oxide (PEO ) (e . g. , POLYOXTM ) . ylcellulose (CMC ), powdered cellulose such as [0057 ] Exemplary hydrophobic polymers include ethyl microcrystalline cellulose , cellulose acetate , ethylcellulose, cellulose ( e . g . , ETHOCELTM , SURELEASE® ), cellulose salts thereof, and combinations thereof; alginates , gums, acetate , methacrylic acid copolymers (e . g ., EUDRAGIT® including heteropolysaccharide gums and homopolysaccha NE 30D ) , ammonio -methacrylate copolymers ( e . g . , ride gums, such as xanthan , tragacanth , pectin , acacia , EUDRAGIT® RL 100 or PO RS100 ) , polyvinyl acetate , karaya , alginates , agar, guar, hydroxypropyl guar , veegum , glyceryl monostearate , fatty acids, such as acetyl tributyl carrageenan , locust bean gum , gellan gum , and derivatives citrate , and combinations and derivatives thereof. thereofrom ; acrylic resins, including polymers and copoly [ 0058 ] The swellable polymer can be incorporated in the mers of acrylic acid , methacrylic acid , methyl acrylate and formulation in proportion from 1 % to 50 % by weight, methyl methacrylate and cross - linked polyacrylic acid preferably from 5 % to 40 % by weight, most preferably from derivatives such as Carbomers ( e . g ., CARBOPOL® , such as 5 % to 20 % by weight. The swellable polymers and binders including CARBOPOL® 716 NF, available in various may be incorporated in the formulation either prior to or US 2018 /0264013 A1 Sep . 20 , 2018 after granulation . The polymers can also be dispersed in mate desired properties of the coating. Suitable levels of organic solvents or hydro - and sprayed during plasticizer range from about 1 % to about 20 % , from about granulation . 3 % to about 20 % , about 3 % to about 5 % , about 7 % to about [0059 ] In some embodiments , the matrix may include a 10 % , about 12 % to about 15 % , about 17 % to about 20 % , or combination of release promoters and solubility enhancers . about 1 % , about 2 % , about 3 % , about 4 % , about 5 % , about The solubility enhancers can be ionic and non - ionic surfac 6 % , about 7 % , about 8 % , about 9 % , about 10 % , about 15 % , tants , complexing agents , hydrophilic polymers , pH modi or about 20 % by weight relative to the total weight of the fiers, such as acidifying agents and alkalinizing agents , as coating , inclusive of all ranges and sub - ranges therebetween . well as molecules that increase the solubility of poorly [ 0067 ] Exemplary plasticizers include, but are not limited soluble drug through molecular entrapment. Several solu to , triacetin , acetylated monoglyceride , oils (castor oil , bility enhancers can be utilized simultaneously. hydrogenated castor oil, rape seed oil , sesame oil, olive oil , 10060 ] Solubility enhancers may include surface active etc . ) ; citrate esters , triethyl citrate , acetyltriethyl citrate agents , such as sodium docusate , sodium lauryl sulfate , acetyltributyl citrate , tributyl citrate , acetyl tri- n - butyl cit sodium stearyl fumarate , Tweens® and Spans (PEO modi rate , diethyl phthalate , dibutyl phthalate , dioctyl phthalate , fied sorbitan monoesters and fatty acid sorbitan esters) , methyl paraben , propyl paraben , butyl paraben , diethyl poly ( oxide ) - polypropylene oxide - poly ( ethylene sebacate , dibutyl sebacate, glyceroltributyrate , substituted oxide) block copolymers (aka PLURONICSTM ); complex triglycerides and glycerides , monoacetylated and diacety ing agents such as low molecular weight polyvinyl pyrroli lated glycerides ( e . g . ,MYVACET® 9 -45 ) , glyceryl monos done and low molecular weight hydroxypropyl methyl cel tearate , glycerol tributyrate , polysorbate 80 , polyethyl lulose ; molecules that aid solubility by molecular eneglycol (such as PEG -4000 , PEG -400 ) , propyleneglycol, entrapment such as cyclodextrins , and pH modifying agents , 1 ,2 -propyleneglycol , glycerin , sorbitol, diethyl oxalate , including acidifying agents such as citric acid , fumaric acid , diethyl malate , diethyl fumarate , diethylmalonate, dibutyl tartaric acid , and hydrochloric acid ; and alkalizing agents succinate , fatty acids, glycerin , sorbitol, diethyl oxalate , such as meglumine and sodium hydroxide. diethyl malate, diethyl maleate , diethyl fumarate , diethyl [0061 ] Solubility enhancing agents typically constitute succinate , diethyl malonate , dioctyl phthalate , dibutyl seba from 1 % to 80 % by weight, preferably from 1 % to 60 % , cate , and mixtures thereof. The plasticizer can have surfac more preferably from 1 % to 50 % , of the dosage form and tant properties , such that it can act as a release modifier. For can be incorporated in a variety of ways . They can be example , non - ionic detergents such at Brij 58 ( polyoxyeth incorporated in the formulation prior to granulation in dry or ylene ( 20 ) cetyl ether ), and the like, can be used . wet form . They can also be added to the formulation after the [0068 ] Plasticizers can be high boiling point organic sol rest of the materials are granulated or otherwise processed . vents used to impart flexibility to otherwise hard or brittle During granulation , solubilizers can be sprayed as solutions polymeric materials and can affect the release profile for the with or without a binder . active agent( s ) . Plasticizers generally cause a reduction in [0062 ] In one embodiment, the extended - release formula the cohesive intermolecular forces along the polymer chains tion comprises a water - insoluble water - permeable polymeric resulting in various changes in polymer properties including coating or matrix comprising one or more water- insoluble a reduction in tensile strength , and increase in elongation water - permeable film - forming over the active core . The and a reduction in the glass transition or softening tempera coating may additionally include one or more water soluble ture of the polymer. The amount and choice of the plasticizer polymers and / or one or more plasticizers. The water - in can affect the hardness of a tablet, for example , and can even soluble polymer coating comprises a barrier coating for affect its dissolution or disintegration characteristics, as well release of active agents in the core , wherein lower molecular as its physical and chemical stability . Certain plasticizers can weight ( viscosity ) grades exhibit faster release rates as increase the elasticity and / or pliability of a coat, thereby compared to higher viscosity grades. decreasing the coat 's brittleness . [0063 ] In preferred embodiments, the water- insoluble [0069 ] In another embodiment, the extended - release for film - forming polymers include one or more alkyl cellulose mulation comprises a combination of at least two gel ethers, such as ethyl celluloses and mixtures thereof, ( e . g ., forming polymers, including at least one non -ionic gel ethyl cellulose grades PR100 , PR45 , PR20 , PR10 and PR7 ; forming polymer and / or at least one anionic gel- forming ETHOCEL® , Dow ) . polymer. The gel formed by the combination of gel- forming [ 0064 ] An exemplary water - soluble polymer such as poly polymers provides controlled release, such that when the vinylpyrrolidone (POVIDONE® ), hydroxypropyl methyl formulation is ingested and comes into contact with the cellulose , hydroxypropyl cellulose and mixtures thereof. gastrointestinal fluids, the polymers nearest the surface [0065 ] In some embodiments , the water- insoluble polymer hydrate to form a viscous gel layer . Because of the high provides suitable properties ( e . g . , extended - release charac viscosity , the viscous layer dissolves away only gradually , teristics , mechanical properties , and coating properties ) exposing the material below to the same process . The mass without the need for a plasticizer . For example , coatings thus dissolves away slowly , thereby slowly releasing the comprising polyvinyl acetate (PVA ) , neutral copolymers of active ingredient into the gastrointestinal fluids . The com acrylate /methacrylate esters such as commercially available bination of at least two gel- forming polymers enables prop Eudragit NE30D from Evonik Industries, ethyl cellulose in erties of the resultant gel, such as viscosity , to be manipu combination with hydroxypropylcellulose , waxes , etc . can lated in order to provide the desired release profile . be applied without plasticizers . [ 0070 ] In a particular embodiment , the formulation com [0066 ] In yet another embodiment, the water- insoluble prises at least one non -ionic gel - forming polymer and at polymer matrix may further include a plasticizer. The least one anionic gel- forming polymer . In another embodi amount of plasticizer required depends upon the plasticizer , ment, the formulation comprises two different non -ionic the properties of the water- insoluble polymer , and the ulti gel - forming polymers . In yet another embodiment, the for US 2018 /0264013 A1 Sep . 20 , 2018 mulation comprises a combination of non - ionic gel- forming therein ( as described above ) or a tablet/ aggregate of active polymers of the same chemistry , but having different solu ingredients , with a coating material , and , optionally , a pore bilities , viscosities, and /or molecular weights ( for example a former and other excipients . The coating material is prefer combination of hydroxyproplyl methylcellulose of different ably selected from a group comprising cellulosic polymers , viscosity grades , such as HPMC K100 and HPMC K15M or such as ethylcellulose (e .g . , SURELEASE® ), methylcellu HPMC K100M ). lose , hydroxypropyl cellulose, hydroxypropylmethyl cellu [ 0071] Exemplary anionic gel forming polymers include , lose , cellulose acetate , and cellulose acetate phthalate ; poly but are not limited to , sodium carboxymethylcellulose (Na vinyl alcohol; acrylic polymers such as polyacrylates, CMC ) , carboxymethyl cellulose ( CMC ), anionic polysac charides such as sodium alginate , alginic acid , pectin , poly polymethacrylates and copolymers thereof, and other water glucuronic acid (poly - d - and - B - 1, 4 - glucuronic acid ), poly based or solvent- based coating materials . The release - con galacturonic acid (pectic acid ) , chondroitin sulfate , trolling coating for a given bead population may be con carrageenan , furcellaran , anionic gums such as xanthan trolled by at least one parameter of the release controlling gum , polymers of acrylic acid or carbomers (Carbopol® coating, such as the nature of the coating , coating level , type 934 , 940 , 974P NF ), Carbopol® copolymers , a Pemulen® and concentration of a pore former, process parameters and polymer , polycarbophil, and others. combinations thereof. Thus , changing a parameter , such as [ 0072 ] Exemplary non - ionic gel - forming polymers a pore former concentration , or the conditions of the curing , include , but are not limited to , Povidone (PVP : polyvinyl allows for changes in the release of active agent ( s ) from any pyrrolidone ), polyvinyl alcohol, copolymer of PVP and given bead population , thereby allowing for selective adjust polyvinyl acetate , HPC (hydroxypropyl cellulose ), HPMC ment of the formulation to a pre- determined release profile . (hydroxypropyl methylcellulose ) , hydroxyethyl cellulose , [0079 ] Pore formers suitable for use in the release con hydroxymethyl cellulose , gelatin , polyethylene oxide, aca trolling coating herein can be organic or inorganic agents , cia , dextrin , starch , polyhydroxyethylmethacrylate and include materials that can be dissolved , extracted or ( PHEMA ) , water soluble nonionic polymethacrylates and leached from the coating in the environment of use . Exem their copolymers , modified cellulose , modified polysaccha plary pore forming agents include , but are not limited to , rides , nonionic gums, nonionic polysaccharides and / or mix organic compounds such as mono - , oligo - , and polysaccha tures thereof. rides including sucrose , glucose , fructose , mannitol, man [0073 ] The formulation may optionally comprise at least nose , galactose , sorbitol, pullulan , dextran ; polymers soluble one excipient, such as a filler, a binder (as described above ) , in the environment of use such as water - soluble hydrophilic a disintegrant, and/ or a flow aid or glidant. polymers , hydroxyalkylcelluloses , carboxyalkylcelluloses, [0074 ] Exemplary fillers include but are not limited to , hydroxypropylmethylcellulose, cellulose ethers, acrylic res lactose , glucose , fructose , sucrose , dicalcium phosphate , ins , polyvinylpyrrolidone , cross- linked polyvinylpyrroli sugar alcohols also known as “ sugar polyol” such as sorbi done , polyethylene oxide , Carbowaxes , Carbopol, and the tol, manitol, lactitol, xylitol, isomalt , erythritol, and hydro like , diols , polyols , polyhydric alcohols , polyalkylene gly genated starch hydrolysates ( a blend of several sugar alco cols , polyethylene glycols , polypropylene glycols , or block hols ), corn s tarch , potato starch , sodium polymers thereof, polyglycols , poly ( a - 2 )alkylenediols ; carboxymethycellulose , ethylcellulose and cellulose acetate , inorganic compounds such as alkali metal salts, enteric polymers , or a mixture thereof. carbonate , sodium chloride , sodium , potassium [0075 ] Exemplary binders, include but are not limited to , chloride, potassium sulfate , potassium phosphate , sodium water - soluble hydrophilic polymers , such as Povidone acetate , sodium citrate , suitable calcium salts , combination ( PVP : polyvinyl pyrrolidone ), copovidone ( a copolymer of thereof, and the like . polyvinylpyrrolidone and polyvinyl acetate ) , low molecular weight HPC (hydroxypropyl cellulose ) low molecular [ 0080 ] The release controlling coating can further com weight HPMC (hydroxypropyl methylcellulose ) , low prise other additives known in the art, such as plasticizers , molecular weight carboxy methyl cellulose , ethylcellulose , anti - adherents , glidants ( or flow aids ), and antifoams. gelatin , polyethylene oxide, acacia , dextrin , [0081 ] In some embodiments , the coated particles or beads aluminum silicate, starch , and polymethacrylates such as may additionally include an “ overcoat, ” to provide , e . g . , Eudragit NE 30D , Eudragit RL , Eudragit RS , Eudragit E , moisture protection , static charge reduction , taste -masking , polyvinyl acetate , and enteric polymers, or mixtures thereof. flavoring, coloring, and /or polish or other cosmetic appeal to [ 0076 ] Exemplary disintegrants include but are not limited the beads . Suitable coating materials for such an overcoat to low - substituted carboxymethyl cellulose sodium , are known in the art , and include , but are not limited to , crospovidone ( cross - linked polyvinyl pyrrolidone) , sodium cellulosic polymers such as hydroxypropylmethylcellulose , carboxymethyl starch (sodium starch glycolate ), cross hydroxypropylcellulose and microcrystalline cellulose , or linked sodium carboxymethyl cellulose (Croscarmellose ), combinations thereof ( for example , various OPADRY® pregelatinized starch ( starch 1500 ) , microcrystalline cellu coating materials ). lose , water insoluble starch , calcium carboxymethyl cellu [0082 ] The coated particles or beads may additionally lose , low substituted hydroxypropyl cellulose , and magne contain enhancers that may be exemplified by, but not sium or aluminum silicate . limited to , solubility enhancers , dissolution enhancers , 00771. Exemplary glidants include but are not limited to , absorption enhancers , permeability enhancers , stabilizers, magnesium , silicon dioxide , talc , starch , titanium dioxide , complexing agents , enzyme inhibitors , p - glycoprotein and the like. inhibitors , and multidrug resistance protein inhibitors . Alter [0078 ] In yet another embodiment, the extended -release natively , the formulation can also contain enhancers that are formulation is formed by coating a water soluble /dispersible separated from the coated particles , for example in a sepa drug -containing particle , such as a bead or bead population rate population of beads or as a powder. In yet another US 2018 /0264013 A1 Sep . 20 , 2018 embodiment, the enhancer( s ) may be contained in a separate [0087 ] In some embodiments , the extended - release formu layer on coated particles either under or above the release lation may comprise a polysaccharide coating that is resis controlling coating . tant to erosion in both the stomach and intestine . Such [0083 ] In other embodiments , the extended - release formu polymers can be only degraded in the colon , which contains lation is formulated to release the active agent (s ) by an a large microflora containing biodegradable enzymes break osmotic mechanism . By way of example , a capsule may be ing down , for example , the polysaccharide coatings to formulated with a single osmotic unit or it may incorporate release the drug contents in a controlled , time- dependent 2 , 3 , 4 , 5 , or 6 push - pull units encapsulated within a hard manner . Exemplary polysaccharide coatings may include , gelatin capsule , whereby each bilayer push - pull unit con for example , amylose , arabinogalactan , chitosan , chondroi tains an osmotic push layer and a drug layer, both sur tin sulfate , cyclodextrin , dextran , guar gum , pectin , xylan , rounded by a semi- permeable membrane . One or more and combinations or derivatives therefrom . orifices are drilled through the membrane next to the drug [0088 ] As used herein , the term " delayed - release” refers to layer. This membrane may be additionally covered with a a medication that does not immediately disintegrate and pH - dependent enteric coating to prevent release until after release the active ingredient( s ) into the body. In some gastric emptying . The gelatin capsule dissolves immediately embodiments , the term " delayed - release ” is used with ref after ingestion . As the push - pull unit( s ) enter the small erence to a drug formulation having a release profile in intestine, the enteric coating breaks down, which then allows which there is a predetermined delay in the release of the fluid to flow through the semi- permeable membrane , swell drug following administration . Delayed - release formula ing the osmotic push compartment to force drugs out tions , such as enteric coatings , prevent drugs having an through the orifice ( s ) at a rate precisely controlled by the rate irritant effect on the stomach , such as aspirin , from dissolv of water transport through the semi- permeable membrane . ing in the stomach . Such coatings are also used to protect Release of drugs can occur over a constant rate for up to 24 acid - unstable drugs from the stomach ' s acidic exposure , hours or more . delivering them instead to a basic pH environment ( intes [0084 ] The osmotic push layer comprises one or more tine ' s pH 5 . 5 and above) where they do not degrade, and osmotic agents creating the driving force for transport of give their desired action . water through the semi- permeable membrane into the core of the delivery vehicle . One class of osmotic agents includes [0089 ] The term “ pulsatile release ” is a type of delayed water- swellable hydrophilic polymers, also referred to as release, which is used herein with reference to a drug " osmopolymers ” and “ hydrogels ,” including , but not limited formulation that provides rapid and transient release of the to , hydrophilic vinyl and acrylic polymers , polysaccharides drug within a short time period immediately after a prede such as calcium alginate , polyethylene oxide (PEO ) , poly termined lag period , thereby producing a “ pulsed ” plasma ethylene glycol (PEG ), polypropylene glycol (PPG ), poly profile of the drug after drug administration . Formulations ( 2 -hydroxyethyl methacrylate ) , poly ( acrylic ) acid , poly may be designed to provide a single pulsatile release or (methacrylic ) acid , polyvinylpyrrolidone (PVP ) , crosslinked multiple pulsatile releases at predetermined time intervals PVP, polyvinyl alcohol (PVA ), PVA /PVP copolymers, PVA / following administration . PVP copolymers with hydrophobic monomers such as [0090 ] A delayed - release or pulsatile release formulation methyl methacrylate and vinyl acetate , hydrophilic polyure generally comprises one or more elements covered with a thanes containing large PEO blocks , sodium croscarmellose , barrier coating , which dissolves , erodes or ruptures follow carrageenan , hydroxyethyl cellulose (HEC ), hydroxypropyl ing a specified lag phase . A barrier coating for delayed cellulose (HPC ) , hydroxypropyl methyl cellulose (HPMC ) , release may consist of a variety of different materials , carboxymethyl cellulose (CMC ) and carboxyethyl, cellulose depending on the objective . In addition , a formulation may (CEC ) , sodium alginate , polycarbophil , gelatin , xanthan comprise a plurality of barrier coatings to facilitate release gum , and sodium starch glycolate . in a temporal manner. The coating may be a sugar coating , [ 0085 ] Another class of osmotic agents includes osmo a film coating (e . g. , based on hydroxypropyl methylcellu gens, which are capable of imbibing water to effect an lose , methylcellulose , methyl hydroxyethylcellulose , osmotic pressure gradient across the semi- permeable mem hydroxypropylcellulose , carboxymethylcellulose, acrylate brane. Exemplary osmogens include, but are not limited to , copolymers , polyethylene glycols and / or polyvinylpyrroli inorganic salts , such as , magnesium done ) , or a coating based on methacrylic acid copolymer , chloride , calcium chloride, sodium chloride , lithium chlo cellulose acetate phthalate , hydroxypropyl methylcellulose ride, potassium sulfate , potassium phosphates , sodium car phthalate , hydroxypropylmethylcellulose acetate succinate , bonate , sodium sulfite , lithium sulfate , potassium chloride , polyvinyl acetate phthalate , shellac , and / or ethylcellulose . and sodium sulfate ; sugars, such as dextrose , fructose , Furthermore , the formulation may additionally include a glucose , inositol , lactose , maltose , mannitol, raffinose , sor time delay material such as , for example , glyceryl monos bitol , sucrose , trehalose, and xylitol; organic acids , such as tearate or glyceryl distearate . ascorbic acid , benzoic acid , fumaric acid , citric acid , maleic [0091 ] In some embodiments , the delayed - release formu acid , sebacic acid , sorbic acid , adipic acid , edetic acid , lation includes an enteric coating comprised one or more glutamic acid , p - toluenesulfonic acid , succinic acid , and polymers facilitating release of active agents in proximal or tartaric acid ; ; and mixtures thereof. distal regions of the gastrointestinal tract. In some embodi [0086 ] Materials useful in forming the semipermeable ments , the enteric coating comprises one or more polymers membrane include various grades of acrylics , vinyls , ethers , having a pH - dependent or pH -sensitive release profile . Typi polyamides , polyesters , and cellulosic derivatives that are cally , the coating resists dissolution in the acidic medium of water- permeable and water - insoluble at physiologically rel the stomach , but dissolves or erodes in more distal regions evant pHs, or are susceptible to being rendered water - of the gastrointestinal tract, such as the small intestine or insoluble by chemical alteration , such as crosslinking . colon . An enteric coating typically resists releases of the US 2018 /0264013 A1 Sep . 20 , 2018 active agents until sometime after a gastric emptying lag GmbH , Germany ) ; copolymers of methacrylic acid -methyl period of about 3 - 4 hours after administration . methacrylate and methyl methacrylate ( EUDRAGIT® FS ) ; [0092 ] In some embodiments , the pH -dependent enteric terpolymers of methacrylic acid , methacrylate , and ethyl coating comprises one or more pH -dependent or pH - sensi acrylate ; cellulose acetate phthalates (CAP ) ; hydroxypropyl tive polymers that maintain their structural integrity at low methylcellulose phthalate (HPMCP ) (e . g. , HP -55 , HP -50 , pH , as in the stomach , but dissolve in higher pH environ HP- 55S , Shinetsu Chemical, Japan ); polyvinyl acetate ments in more distal regions of the gastrointestinal tract, phthalates (PVAP ) ( e . g ., COATERIC® , OPADRY® enteric such as the small intestine , where the drug contents are white OY- P -7171 ) ; polyvinylbutyrate acetate ; cellulose released . For purposes of the present invention , “ pH - depen acetate succinates (CAS ) ; hydroxypropyl methylcellulose dent" or " pH -sensitive ” is defined as having characteristics acetate succinate (HPMCAS ) , e . g ., HPMCAS LF Grade , ( e. g ., dissolution ) which vary according to environmental MF Grade, HF Grade , including AQOAT® LF and pH . Exemplary pH - dependent polymers include , but are not AQOAT® MF (Shin - Etsu Chemical, Japan ) ; Shinetsu limited to , methacarylic acid copolymers , methacrylic acid Chemical, Japan ); shellac ( e .g . , MARCOATTM 125 & MAR methylmethacrylate copolymers ( e . g . , EUDRAGIT® L100 COATTM 125N ) ; vinyl acetate -maleic anhydride copolymer ; ( Type A ), EUDRAGIT® S100 ( Type B ) , Rohm GmbH , styrene- maleic monoester copolymer ; carboxymethyl ethyl Germany ; methacrylic acid - ethyl acrylate copolymers ( e . g ., cellulose (CMEC , Freund Corporation , Japan ) ; cellulose EUDRAGIT® L100 -55 ( Type C ) and EUDRAGIT® L30D acetate phthalates (CAP ) ( e . g ., AQUATERIC® ) ; cellulose 55 copolymer dispersion , Rohm GmbH , Germany ) ; copo acetate trimellitates (CAT ) ; and mixtures of two or more lymers ofmethacrylic acid -methyl methacrylate and methyl thereof at weight ratios between about 2 : 1 to about 5 : 1 , such methacrylate (EUDRAGIT® FS ) ; terpolymers of meth as, for instance , a mixture of EUDRAGIT® L 100 - 55 and acrylic acid , methacrylate , and ethyl acrylate ; cellulose EUDRAGIT® S 100 at a weight ratio of about 3 : 1 to about acetate phthalates (CAP ); hydroxypropyl methylcellulose 2 : 1 , or a mixture of EUDRAGIT® L 30 D -55 and phthalate (HPMCP ) ( e . g . , HP - 55 , HP -50 , HP - 55S , Shinetsu EUDRAGIT® FS at a weight ratio of about 3 : 1 to about 5 : 1. Chemical, Japan ) ; polyvinyl acetate phthalates (PVAP ) ( e . g . , [ 0096 ] These polymers may be used either alone or in COATERIC® , OPADRY® enteric white OY - P -7171 ) ; cel combination , or together with polymers other than those lulose acetate succinates (CAS ) ; hydroxypropyl methylcel mentioned above . Preferred enteric pH - dependent polymers lulose acetate succinate (HPMCAS ) , e . g ., HPMCAS LF are the pharmaceutically acceptable methacrylic acid copo Grade , MF Grade, HF Grade, including AQOAT® LF and lymers . These copolymers are anionic polymers based on AQOAT® MF ( Shin - Etsu Chemical, Japan ) ; Shinetsu methacrylic acid and methyl methacrylate and , preferably , Chemical, Japan ) ; shellac (e . g ., MarcoatTM 125 & Mar have a mean molecular weight of about 135 , 000 . A ratio of coatTM 125N ) ; carboxymethyl ethylcellulose (CMEC , Fre free carboxyl groups to methyl- esterified carboxyl groups in und Corporation , Japan ), cellulose acetate phthalates (CAP ) these copolymers may range, for example , from 1 : 1 to 1 : 3 , ( e . g . , AQUATERIC® ) ; cellulose acetate trimellitates ( CAT) ; e . g . around 1 : 1 or 1 : 2 . Such polymers are sold under the and mixtures of two or more thereof at weight ratios between trade name Eudragit® such as the Eudragit L series e . g . , about 2 : 1 to about 5 : 1 , such as, for instance, a mixture of Eudragit L 12 .5® , Eudragit L 12 . 5P® , Eudragit L100 , EUDRAGIT® L 100 - 55 and EUDRAGIT® S 100 at a Eudragit L 100 - 55® , Eudragit L - 30D® , Eudragit L - 30 weight ratio of about 3 : 1 to about 2 : 1 , or a mixture of D - 55® , the Eudragit S? series e . g . , Eudragit S 12 . 5® , EUDRAGIT® L 30 D - 55 and EUDRAGIT® FS at a weight Eudragit S 12 . 5P® , Eudragit S100® . The release promoters ratio of about 3 : 1 to about 5 : 1 . are not limited to pH dependent polymers . Other hydrophilic [0093 ] pH - dependent polymers typically exhibit a charac molecules that dissolve rapidly and leach out of the dosage teristic pH optimum for dissolution . In some embodiments , form quickly leaving a porous structure can be also be used the pH - dependent polymer exhibits a pH optimum between for the same purpose . about 5 . 0 and 5 . 5 , between about 5 . 5 and 6 . 0 , between about [0097 ] In some embodiments , the delayed - release formu 6 . 0 and 6 . 5 , or between about 6 . 5 and 7 . 0 . In other embodi lation comprises a polymeric matrix that can provide for ments , the pH -dependent polymer exhibits a pH optimum of release of the drug after a certain time, independent of the 25 . 0 , of 25 . 5 , of 26 . 0 , of 26 . 5 , or of 27 . 0 . PH . For purposes of the present invention , " pH - indepen [0094 ] In certain embodiment, the coating methodology dent" is defined as having characteristics ( e . g . , dissolution ) employs the blending of one or more pH -dependent and one which are substantially unaffected by pH . PH - independent or more pH - independent polymers . The blending of pH polymers are often referred to in the context of “ time dependent and pH - independent polymers can reduce the controlled ” or “ time- dependent ” release profiles. release rate of active ingredients once the soluble polymer [0098 ] ApH - independent polymermay be used to coat the has reached its optimum pH of solubilization . active agent and / or provide a polymer for a hydrophilic [0095 ] Exemplary release -promoting agents include pH matrix in the extended - release coating thereover . The pH dependent enteric polymers that remain intact at pH value independent polymer may be water - insoluble or water lower than about 4 . 0 and dissolve at pH values higher than soluble . Exemplary water insoluble pH - independent poly 4 . 0 , preferably higher than 5 . 0 , most preferably about 6 . 0 , mers include , but are not limited to , neutralmethacrylic acid are considered useful as release -promoting agents for this esters with a small portion of trimethylammonioethylmeth invention . Exemplary pH - dependent polymers include, but acrylate chloride ( e . g ., EUDRAGIT® RS and are not limited to , methacarylic acid copolymers , meth EUDRAGIT® RL ; neutral ester dispersions without any acrylic acid -methyl methacrylate copolymers ( e . g ., functional groups ( e. g ., EUDRAGIT® NE30D and EUDRAGIT® L100 ( Type A ) , EUDRAGIT® S100 ( Type EUDRAGIT® NE30 ) ; cellulosic polymers, such as ethyl B ) , Rohm GmbH , Germany ; methacrylic acid - ethyl acrylate cellulose , hydroxyl ethyl cellulose , cellulose acetate or mix copolymers ( e . g . , EUDRAGIT® L100 -55 ( Type C ) and tures and other pH independent coating products . Exemplary EUDRAGIT® L30D - 55 copolymer dispersion , Rohm water soluble pH independent polymers include hydroxy US 2018 /0264013 A1 Sep . 20 , 2018

alkyl cellulose ethers, such as hydroxypropyl methylcellu having a viscosity of about 1000 -7000 mPa s as a 1 % w /w lose (HPMC ) , and hydroxypropyl cellulose ( HPC ) ; polyvi aqueous solution (25° C . ) ; hydroxypropyl methylcellulose nylpyrrolidone (PVP ), methylcellulose, OPADRY® amb , having a viscosity of about 1000 or higher, preferably 2 , 500 guar gum , xanthan gum , gum arabic , hydroxyethyl cellulose or higher to a maximum of 25 , 000 mPa as a 2 % w / v aqueous and ethyl acrylate and methyl methacrylate copolymer dis solution ; polyvinylpyrrolidone having a viscosity of about persion or combinations thereof. 300 - 700 mPa. s as a 10 % w / v aqueous solution at 20° C . ; and 100991 In some embodiments , a " time -controlled ” or combinations thereof. “ time- dependent ” delayed - release profile can be obtained [0102 ] Alternatively , the release time of the drugs can be using a water insoluble capsule body containing one or more controlled by a disintegration lag time depending on the active agents , wherein the capsule body closed at one end balance between the tolerability and thickness of a water with an insoluble , but permeable and swellable hydrogel insoluble polymer membrane (such as ethyl cellulose , EC ) plug. Upon contact with gastrointestinal fluid or dissolution containing predefined micropores at the bottom of the body medium , the plug swells , pushing itself out of the capsule and the amount of a swellable excipient, such as low and releasing the drugs after a pre -determined lag time, substituted hydroxypropyl cellulose ( L -HPC ) and sodium which can be controlled by e .g ., the position and dimensions glycolate . After oral administration , GI fluids permeate of the plug . The capsule body may be further coated with an through the micropores, causing swelling of the swellable outer pH -dependent enteric coating keeping the capsule excipients , which produces an inner pressure disengaging intact until it reaches the small intestine . Suitable plug the capsular components , including a first capsule body materials include , for example , polymethacrylates, erodible containing the swellable materials , a second capsule body compressed polymers ( e. g ., HPMC , polyvinyl alcohol) , con containing the drugs, and an outer cap attached to the first gealed melted polymer ( e . g ., glyceryl mono oleate ) and capsule body . enzymatically controlled erodible polymers ( e . g ., polysac [0103 ] The enteric layer may further comprise anti - tacki charides, such as amylose , arabinogalactan , chitosan , chon ness agents , such as talc or glyceryl monostearate and / or droitin sulfate , cyclodextrin , dextran , guar gum , pectin and plasticizers . The enteric layer may further comprise one or xylan ) . more plasticizers including , but not limited to , triethyl [0100 ] In other embodiments , capsules or bilayered tablets citrate , acetyl triethyl citrate , acetyltributyl citrate , polyeth may be formulated to contain a drug - containing core , cov ylene glycol acetylated monoglycerides , glycerin , triacetin , ered by a swelling layer, and an outer insoluble , but semi propylene glycol, phthalate esters ( e . g ., diethyl phthalate , permeable polymer coating or membrane. The lag time prior dibutyl phthalate ), titanium dioxide , ferric oxides , castor oil , to rupture can be controlled by the permeation and mechani sorbitol and dibutyl sebacate. cal properties of the polymer coating and the swelling [0104 ] In another embodiment, the delayed - release formu behavior of the swelling layer. Typically, the swelling layer lation employs a water - permeable but insoluble film coating comprises one or more swelling agents , such as swellable to enclose the active ingredient and an osmotic agent. As hydrophilic polymers that swell and retain water in their water from the gut slowly diffuses through the film into the structures . core , the core swells until the film bursts , thereby releasing 10101 ] Exemplary water swellable materials to be used in the active ingredients. The film coating may be adjusted to the delayed -release coating include , but are not limited to , permit various rates of water permeation or release time. polyethylene oxide ( having e . g ., an average molecular [0105 ] In another embodiment, the delayed - release formu weight between 1, 000 , 000 to 7 , 000 ,000 , such as lation employs a water - impermeable tablet coating whereby POLYOX® ) , methylcellulose , hydroxypropyl cellulose , water enters through a controlled aperture in the coating hydroxypropyl methylcellulose ; polyalkylene oxides having until the core bursts . When the tablet bursts , the drug a weight average molecular weight of 100 ,000 to 6 ,000 , 000 , contents are released immediately or over a longer period of including but not limited to poly (methylene oxide ), poly time. These and other techniques may be modified to allow (butylene oxide ) ; poly (hydroxy alkylmethacrylate ) having a for a pre -determined lag period before release of drugs is molecular weight of from 25 ,000 to 5 ,000 , 000 ; poly ( vinyl) initiated alcohol, having a low acetal residue, which is cross - linked [0106 ] In another embodiment, the active agents are deliv with glyoxal, formaldehyde or glutaraldehyde and having a ered in a formulation to provide both delayed - release and degree of polymerization of from 200 to 30 ,000 ; mixtures of extended - release (delayed - sustained ) . The term " delayed methyl cellulose , cross -linked agar and carboxymethyl cel extended - release ” is used herein with reference to a drug lulose ; hydrogel forming copolymers produced by forming formulation providing pulsatile release of active agents at a a dispersion of a finely divided copolymer ofmaleic anhy pre -determined time or lag period following administration , dride with styrene , ethylene , propylene , butylene or isobu which is then followed by extended - release of the active tylene cross - linked with from 0 .001 to 0 . 5 moles of saturated agents thereafter. In some embodiments, the delayed cross - linking agent per mole of maleic anyhydride in the extended - release formulation includes an extended - release copolymer; CARBOPOL® acidic carboxy polymers having formulation coated with an enteric coating, which is a barrier a molecular weight of 450 , 000 to 4 ,000 ,000 ; CYANA applied to oral medication that prevents release of medica MER® polyacrylamides ; cross - linked water swellable tion before it reaches the small intestine . indenemaleicanhydride polymers ; GOODRITE® poly [0107 ] As used herein , the term " orally disintegrating acrylic acid having a molecular weight of 80 ,000 to 200 ,000 ; formulation ” refers to drug formulations that rapidly disin starch graft copolymers; AQUA - KEEPS® acrylate polymer tegrate or dissolve in oral cavity . Orally disintegrating polysaccharides composed of condensed glucose units such formulations differ from traditional tablets in that they are as diester cross- linked polyglucan ; carbomers having a designed to be dissolved on the tongue rather than swal viscosity of 3 ,000 to 60 , 000 mPa as a 0 . 5 % - 1 % w / v aqueous lowed whole . In some embodiments , the orally disintegrat solution ; cellulose ethers such as hydroxypropylcellulose ing formulations are designed to completely disintegrate or US 2018 /0264013 A1 Sep . 20 , 2018 dissolve in oral cavity without the aid of additional water 30 % , 35 % , about 40 % , of the total dosage of the active ( i. e ., in saliva only ) in 5 , 10 , 20 , 30 , 60 , 90 , 120 , 180 , 240 agent( s ) to be delivered by the pharmaceutical formulation . or 300 seconds . The extended -release or delayed - extended - release compo [0108 ] In some embodiments , the pharmaceutical compo nent provides about 60 % , 65 % , 70 % , 75 % or 80 % of the sition is formulated in an orally disintegrating formulation . total dosage of the active agent ( s ) to be delivered by the In certain embodiments , the orally disintegrating formula formulation . In some embodiments , the delayed - extended tion is designed to completely disintegrate or dissolve in oral release component comprises a barrier coating, such as cavity without the aid of additional water ( i. e ., in saliva enteric coating , to delay the release of the active agent. only ) in 5 , 10 , 20 , 30 , 60 , 90 , 120 , 180 , 240 or 300 seconds . [0112 ] In some embodiments, immediate - release , 10109 ]. In some embodiments , the orally disintegrating extended -release , delayed -release , or delayed -extended -re formulation is in the form of an orally disintegrating tablet. lease formulations comprises an active core comprised of Orally disintegrating tablets may be manufactured using one or more inert particles, each in the form of a bead , pellet , loose compression tableting , a process which is not very pill , granular particle , microcapsule , microsphere , micro different than the manufacturing method used for traditional granule , nanocapsule , or nanosphere coated on its surfaces tablets and lyophilization processes . In loose compression , with drugs in the form of e . g . , a drug - containing film orally disintegrating formulation is compressed at much forming composition using , for example , fluid bed tech lower forces (4 - 20 kN ) than traditional tablets . In some niques or other methodologies known to those of skill in the embodiments , the orally disintegrating formulation contains art . The inert particle can be of various sizes , so long as it some form of sugar, such as mannitol, to improve mouth is large enough to remain poorly dissolved . Alternatively , feel. In some embodiments , the orally disintegrating tablet is the active core may be prepared by granulating and milling produced using lyophilized orally disintegrating formula and / or by extrusion and spheronization of a polymer com tion . position containing the drug substance . [0110 ] In some embodiments , the pharmaceutical compo [0113 ] The amount of drug in the core will depend on the sition of the present application is formulated for extended dose that is required , and typically varies from about 5 to 90 release , delayed - release or delayed extended - release and wt % . Generally , the polymeric coating on the active core comprises 100 % of the total dosage of a given active agent will be from about 1 to 50 % based on the weight of the administered in a single unit dose . In other embodiments , the coated particle , depending on the lag time and type of pharmaceutical composition comprises an extended /de release profile required and / or the polymers and coating layed -release component and an immediate -release compo solvents chosen . Those skilled in the art will be able to select nent. In some embodiments , the immediate - release compo an appropriate amount of drug for coating onto or incorpo nent and the extended /delayed - release component contain rating into the core to achieve the desired dosage . In one the same active ingredient. In other embodiments , the imme embodiment, the inactive core may be a sugar sphere or a diate -release component and the extended delayed -release buffer crystal or an encapsulated buffer crystal such as component contain different active ingredients ( e . g . , an calcium carbonate, sodium bicarbonate , fumaric acid , tar analgesic in one component and an antimuscarinic agent in taric acid , etc . which alters the microenvironment of the another component ) . In some embodiments , the first and drug to facilitate its release . second components each contains an analgesic selected from [0114 ] In some embodiments , for example , delayed - re the group consisting of aspirin , ibuprofen , naproxen sodium , lease or delayed - extended - release compositions may formed indomethacin , nabumetone , and acetaminophen . In other by coating a water soluble / dispersible drug - containing par embodiments , the extended / delayed -release component is ticle , such as a bead , with a mixture of a water insoluble coated with an enteric coating . In other embodiments , the polymer and an enteric polymer, wherein the water insoluble immediate -release component and /or the extended / delayed polymer and the enteric polymer may be present at a weight release component further comprises an antimuscarinic ratio of from 4 : 1 to 1 : 1 , and the total weight of the coatings agent selected from the group consisting of oxybutynin , is 10 to 60 weight % based on the total weight of the coated solifenacin , darifenacin and atropine . In other embodiments , beads. The drug layered beads may optionally include an the analgesic agent in each component is administered orally inner dissolution rate controlling membrane of ethylcellu at a daily dose of 5 mg - 2000 mg, 20 mg - 1000 mg, 50 lose . The composition of the outer layer, as well as the mg- 500 mg or 250 - 1000 mg. In other embodiments , the individual weights of the inner and outer layers of the immediate - release component and /or the extended / delayed polymeric membrane, are optimized for achieving desired release component further comprises an antidiuretic agent, circadian rhythm release profiles for a given active , which an antimuscarinic agent or both . In other embodiments, the are predicted based on in vitro / in vivo correlations. treatment method includes administering to a subject a f0115 ] In other embodiments the formulations may com diuretic at least 8 hours prior to a target time , such as prise a mixture of immediate -release drug -containing par bedtime, and administering to the subject the pharmaceutical ticles without a dissolution rate controlling polymer mem composition comprising the immediate -release component brane and delayed - extended - release beads exhibiting , for and / or the extended /delayed - release component within 2 example , a lag time of 2 - 4 hours following oral administra hours prior to the target time. tion , thus providing a two -pulse release profile. [0111 ] In other embodiments , the immediate - release com [ 0116 ] In some embodiments , the active core is coated ponent provides about 5 - 50 % of the total dosage of the with one or more layers of dissolution rate - controlling active agent( s ) and the extended - release or the delayed polymers to obtain desired release profiles with or without a extended - release component provides 50 - 95 % of the total lag time . An inner layer membrane can largely control the dosage of the active agent( s ) to be delivered by the phar rate of drug release following imbibition of water or body maceutical formulation . For example , the immediate - release fluids into the core , while the outer layer membrane can component may provide about 20 -40 % , or about 20 % , 25 % , provide for a desired lag time ( the period of no or little drug US 2018 /0264013 A1 Sep . 20 , 2018 release following imbibition of water or body fluids into the pharmaceutical composition is administered immediately core ) . The inner layer membrane may comprise a water before bedtime. Preferably , the pharmaceutical composition insoluble polymer, or a mixture of water insoluble and water is administered orally . Suitable compositions for oral admin soluble polymers. istration include, but are not limited to : tablets , coated [0117 ] The polymers suitable for the outer membrane , tablets , dragees, capsules, powders , granulates and soluble which largely controls the lag time of up to 6 hours may tablets , and liquid forms, for example , suspensions, disper comprise an enteric polymer, as described above , and a sions or solutions. water insoluble polymer at 10 to 50 wt % of the weight. The [0122 ] Most enteric coatings work by presenting a surface ratio of water insoluble polymer to enteric polymer may that is stable at the highly acidic pH found in the stomach , vary from 4 : 1 to 1 :2 , preferably the polymers are present at but breaks down rapidly at a less acidic ( relatively more a ratio of about 1 : 1 . The water insoluble polymer typically basic ) pH . Therefore , an enteric coated pill will not dissolve used is ethylcellulose . in the acidic juices of the stomach (pH ~ 3 ), but they will in [0118 ] Exemplary water insoluble polymers include eth the alkaline (pH 7 - 9 ) environment present in the small ylcellulose , polyvinyl acetate (Kollicoat SR # OD from intestine . Examples of enteric coating materials include , but BASF ), neutral copolymers based on ethyl acrylate and are not limited to , methyl acrylate -methacrylic acid copo methylmethacrylate , copolymers of acrylic and methacrylic lymers , cellulose acetate succinate , hydroxy propyl methyl acid esters with quaternary ammonium groups such as cellulose phthalate , hydroxy propyl methyl cellulose acetate EUDRAGIT® NE , RS and RS30D , RL or RL30D and the succinate (hypromellose acetate succinate ) , polyvinyl like. Exemplary water soluble polymers include low acetate phthalate ( PVAP ) , methyl methacrylate -methacrylic molecular weight HPMC , HPC , methylcellulose , polyethyl acid copolymers , sodium alginate and stearic acid . ene glycol (PEG of molecular weight> 3000 ) at a thickness [0123 ] In some embodiments , the pharmaceutical compo ranging from 1 weight % up to 10 weight % depending on sition is orally administered from a variety of drug formu the solubility of the active in water and the solvent or latex lations designed to provide delayed - release . Delayed oral suspension based coating formulation used . The water dosage forms include, for example , tablets , capsules , insoluble polymer to water soluble polymer may typically caplets , and may also comprise a plurality of granules, vary from 95 : 5 to 60 : 40 , preferably from 80 : 20 to 65 : 35 . beads, powders or pellets that may or may not be encapsu 10119 ] In some embodiments, AMBERLITETM IRP69 lated . Tablets and capsules represent the most convenient resin is used as an extended - release carrier. AMBERLITETM oral dosage forms, in which case solid pharmaceutical IRP69 is an insoluble , strongly acidic , sodium form cation carriers are employed . exchange resin that is suitable as carrier for cationic (basic ) [0124 ] In a delayed -release formulation , one or more substances . In other embodiments , DUOLITETM AP143 / barrier coatings may be applied to pellets , tablets, or cap 1093 resin is used as an extended -release carrier. DUO sules to facilitate slow dissolution and concomitant release LITETM AP143 / 1093 is an insoluble , strongly basic, anion of drugs into the intestine . Typically , the barrier coating exchange resin that is suitable as a carrier for anionic contains one or more polymers encasing, surrounding , or ( acidic ) substances . forming a layer, or membrane around the therapeutic com 10120 ] When used as a drug carrier , AMBERLITE IRP69 position or active core . or / and DUOLITETM AP143 / 1093 resin provide a means for [0125 ] In some embodiments , the active agents are deliv binding medicinal agents onto an insoluble polymeric ered in a formulation to provide delayed - release at a pre matrix . Extended - release is achieved through the formation determined time following administration . The delay may be of resin - drug complexes ( drug resinates ). The drug is up to about 10 minutes, about 20 minutes , about 30 minutes , released from the resin in vivo as the drug reaches equilib about 1 hour, about 2 hours , about 3 hours, about 4 hours , rium with the high electrolyte concentrations, which are about 5 hours , about 6 hours , or longer. typical of the gastrointestinal tract. More hydrophobic drugs [0126 ] In other embodiments , the delayed - release is will usually elute from the resin at a lower rate, owing to caused by an osmotic mechanism . By way of example , a hydrophobic interactions with the aromatic structure of the capsule may be formulated with a single osmotic unit or it cation exchange system . may incorporate 2 , 3 , 4 , 5 , or 6 push - pull units encapsulated [0121 ] The pharmaceutical composition may be adminis within a hard gelatin capsule , whereby each bilayer push tered daily or administered on an as needed basis . In certain pull unit contains an osmotic push layer and a drug layer , embodiments , the pharmaceutical composition is adminis both surrounded by a semi- permeable membrane . One or tered to the subject prior to bedtime. In some embodiments , more orifices are drilled through the membrane next to the the pharmaceutical composition is administered immedi drug layer . This membranemay be additionally covered with ately before bedtime. In some embodiments , the pharma a pH - dependent enteric coating to prevent release until after ceutical composition is administered within about two hours gastric emptying . The gelatin capsule dissolves immediately before bedtime, preferably within about one hour before after ingestion . As the push pull unit ( s ) enter the small bedtime. In another embodiment, the pharmaceutical com intestine , the enteric coating breaks down , which then allows position is administered about two hours before bedtime. In fluid to flow through the semi- permeable membrane , swell a further embodiment , the pharmaceutical composition is ing the osmotic push compartment to force drugs out administered at least two hours before bedtime. In another through the orifice ( s ) at a rate precisely controlled by the rate embodiment, the pharmaceutical composition is adminis of water transport through the semi- permeable membrane . tered about one hour before bedtime. In a further embodi Release of drugs can occur over a constant rate for up to 24 ment, the pharmaceutical composition is administered at hours or more . least one hour before bedtime. In a still further embodiment, [0127 ] The osmotic push layer comprises one or more the pharmaceutical composition is administered less than osmotic agents creating the driving force for transport of one hour before bedtime. In still another embodiment, the water through the semi- permeable membrane into the core US 2018 /0264013 A1 Sep . 20 , 2018 13 of the delivery vehicle . One class of osmotic agents includes [0133 ] In some embodiments , the pharmaceutical compo water -swellable hydrophilic polymers , also referred to as sition comprises a plurality of active ingredients selected " osmopolymers” and “ hydrogels ,” including , but not limited from the group consisting of analgesics , antimuscarinic to , hydrophilic vinyl and acrylic polymers , polysaccharides agents , antidiuretics and spasmolytics . Examples of spas such as calcium alginate , polyethylene oxide ( PEO ) , poly molytics include , but are not limited to , carisoprodol , ben ethylene glycol (PEG ), polypropylene glycol (PPG ), poly zodiazepines , baclofen , cyclobenzaprine , metaxalone , ( 2 - hydroxyethyl methacrylate ), poly ( acrylic ) acid , poly methocarbamol, clonidine , clonidine analog , and dantrolene . (methacrylic ) acid , polyvinylpyrrolidone (PVP ) , crosslinked In some embodiments , the pharmaceutical composition PVP , polyvinyl alcohol (PVA ), PVA / PVP copolymers , PVA / comprises one or more analgesics. In other embodiments , PVP copolymers with hydrophobic monomers such as the pharmaceutical composition comprises ( 1 ) one or more methylmethacrylate and vinyl acetate , hydrophilic polyure analgesics , and ( 2 ) one or more other active ingredients thanes containing large PEO blocks , sodium croscarmellose , selected from the group consisting of antimuscarinic agents , carrageenan , hydroxyethyl cellulose (HEC ), hydroxypropyl antidiuretics and spasmolytics . In another embodiment, the cellulose (HPC ) , hydroxypropyl methyl cellulose (HPMC ) , pharmaceutical composition comprises ( 1 ) one or two anal carboxymethyl cellulose (CMC ) and carboxyethyl, cellulose gesics and ( 2 ) one or two antimuscarinic agents . In another ( CEC ) , sodium alginate , polycarbophil , gelatin , Xanthan embodiment, the pharmaceutical composition comprises ( 1 ) gum , and sodium starch glycolate. one or two analgesics and ( 2 ) one or two antidiuretics. In [0128 ] Another class of osmotic agents includes osmo another embodiment, the pharmaceutical composition com gens, which are capable of imbibing water to affect an prises (1 ) one or two analgesics and (2 ) one or two spas osmotic pressure gradient across the semi- permeable mem molytics . In yet another embodiment, the pharmaceutical brane . Exemplary osmogens include , but are not limited to , composition comprises ( 1 ) one or two analgesics, ( 2 ) one or inorganic salts , such as magnesium sulfate , magnesium two antimuscarinic agents , and ( 3 ) one or two antidiuretics. chloride , calcium chloride , sodium chloride, lithium chlo [0134 ] In some embodiments , the pharmaceutical compo ride, potassium sulfate , potassium phosphates , sodium car sition comprises acetaminophen . In some embodiments , the bonate , sodium sulfite , lithium sulfate , potassium chloride, pharmaceutical composition comprises ibuprofen . In some and sodium sulfate ; sugars , such as dextrose , fructose , embodiments , the pharmaceutical composition comprises glucose , inositol, lactose , maltose , mannitol, raffinose , sor acetaminophen and ibuprofen . In some embodiments , the bitol, sucrose , trehalose , and xylitol; organic acids, such as pharmaceutical composition comprises acetaminophen and ascorbic acid , benzoic acid , fumaric acid , citric acid , maleic ibuprofen as the only active ingredients in the composition . acid , sebacic acid , sorbic acid , adipic acid , edetic acid , In some embodiments , pharmaceutical composition further glutamic acid , p - toluenesulfonic acid , succinic acid , and comprises one or more active agents selected from the group tartaric acid ; urea , and mixtures thereof . consisting of anti- insomnia agents , antimuscarinic agents , [0129 ] Materials useful in forming the semipermeable antidiuretic agents , spasmolytics , a -blockers , 5a -reductase membrane include various grades of acrylics , vinyls , ethers , inhibitors , phosphodiesterase type 5 (PDE5 ) inhibitors and polyamides, polyesters , and cellulosic derivatives that are prostaglandin (PD ) pathway inhibitors . water- permeable and water- insoluble at physiologically rel 10135 ] In one embodiment, the plurality of active ingre evant pHs, or are susceptible to being rendered water dients are formulated for immediate -release . In other insoluble by chemical alteration , such as crosslinking . embodiment, the plurality of active ingredients are formu [0130 ] In another embodiment, the delay release formu lated for extended -release . In other embodiment, the plural lation employs a water - impermeable tablet coating whereby ity of active ingredients are formulated for both immediate water enters through a controlled aperture in the coating release and extended -release ( e . g . , a first portion of each until the core bursts . When the tablet bursts, the drug active ingredient is formulated for immediate - release and a contents are released immediately or over a longer period of second portion of each active ingredient is formulated for time. These and other techniques may be modified to allow extended - release ) . In yet other embodiment, some of the for a pre - determined lag period before release of drugs is plurality of active ingredients are formulated for immediate initiated . release and some of the plurality of active ingredients are [0131 ] Various coating techniques may be applied to gran formulated for extended - release ( e . g ., active ingredients A , ules, beads, powders or pellets , tablets , capsules or combi B , C are formulated for immediate -release and active ingre nations thereof containing active agents to produce different dients C and D are formulated for extended - release ) . In and distinct release profiles . In some embodiments , the some other embodiments , the immediate - release component pharmaceutical composition is in a tablet or capsule form and / or the extended - release component is further coated containing a single coating layer. In other embodiments , the with a delayed - release coating, such as an enteric coating . pharmaceutical composition is in a tablet or capsule form [0136 ] In certain embodiments , the pharmaceutical com containing multiple coating layers . position comprises an immediate - release component and an [ 0132 ] In some embodiments , the pharmaceutical compo extended -release component. The immediate - release com sition of the present application further comprises a release ponent may comprise one or more active agents selected promoting agent. The release -promoting agent can be incor from the group consisting of analgesics, anti- insomnia porated in an amount from 10 % to 90 % , preferably from agents , antimuscarinic agents , antidiuretic agents , spasmo 20 % to 80 % and most preferably from 30 % to 70 % by lytics , a - blockers , 5a - reductase inhibitors, phosphodies weightof the dosage unit . The agent can be incorporated into terase type 5 ( PDE5 ) inhibitors and prostaglandin (PD ) the formulation either prior to or after granulation . The pathway inhibitors . release - promoting agent can be added into the formulation [0137 ] The extended - release component may comprise either as a dry material, or it can be dispersed or dissolved one or more active ingredients selected from the group in an appropriate solvent, and dispersed during granulation . consisting of analgesics, anti- insomnia agents , antimuscar US 2018 /0264013 A1 Sep . 20 , 2018 14 inic agents, antidiuretic agents , spasmolytics , a -blockers , 10142 ] In some embodiments , the immediate - release or 5a - reductase inhibitors , phosphodiesterase type 5 (PDE5 ) delayed - release formulation comprises an active core com inhibitors and prostaglandin (PD ) pathway inhibitors prised of one or more inert particles , each in the form of a [0138 ] In some embodiments , the immediate -release com bead , pellet , pill , granular particle , microcapsule , micro ponent and the extended - release component have exactly the sphere , microgranule , nanocapsule , or nanosphere coated on same active ingredients . In other embodiments , the imme its surfaces with drugs in the form of e . g . , a drug - containing diate - release component and the extended - release compo film - forming composition using , for example , fluid bed nent have different active ingredients . In yet other embodi techniques or other methodologies known to those of skill in ments , the immediate -release component and the extended the art. The inert particle can be of various sizes , so long as release component have one or more common active it is large enough to remain poorly dissolved . Alternatively, ingredients . In some other embodiments , the immediate the active core may be prepared by granulating and milling release component and /or the extended -release component and / or by extrusion and spheronization of a polymer com is further coated with a delayed - release coating, such as an position containing the drug substance . enteric coating . [0143 ] The amount of drug in the core will depend on the [0139 ] In one embodiment, the pharmaceutical composi dose that is required, and typically varies from about 5 to 90 tion comprises two active ingredients ( e . g . , two analgesic wt % . Generally, the polymeric coating on the active core agents , or a mixture of one analgesic agent and one anti will be from about 1 to 50 % based on the weight of the muscarinic agent or antidiuretic or spasmolytic ) , formulated coated particle , depending on the lag time and type of for immediate -release at about the same time. In another release profile required and / or the polymers and coating embodiment, the pharmaceutical composition comprises solvents chosen . Those skilled in the art will be able to select two active ingredients , formulated for extended -release at an appropriate amount of drug for coating onto or incorpo about the same time. In another embodiment, the pharma rating into the core to achieve the desired dosage . In one ceutical composition comprises two active ingredients for embodiment, the inactive core may be a sugar sphere or a mulated as two extended - release components , each provid buffer crystal or an encapsulated buffer crystal such as ing a different extended - release profile . For example , a first calcium carbonate , sodium bicarbonate , fumaric acid , tar extended - release component releases a first active ingredient taric acid , etc . which alters the microenvironment of the at a first release rate and a second extended - release compo drug to facilitate its release . nent releases a second active ingredient at a second release [0144 ] In some embodiments , the delayed - release formu rate . In another embodiment, the pharmaceutical composi lation is formed by coating a water soluble / dispersible tion comprises two active ingredients formulated as two drug -containing particle , such as a bead , with a mixture of delayed -release components , each providing a different a water insoluble polymer and an enteric polymer, wherein delayed -release profile . For example , a first delayed -release the water insoluble polymer and the enteric polymer may be component releases a first active ingredient at a first time present at a weight ratio of from 4 : 1 to 1 : 1 , and the total point and a second delayed - release component releases a weight of the coatings is 10 to 60 weight % based on the total second active ingredient at a second time point. In another weight of the coated beads. The drug layered beads may embodiment, the pharmaceutical composition comprises optionally include an inner dissolution rate controllingmem two active ingredients , one is formulated for immediate brane of ethylcellulose . The composition of the outer layer , release and the other is formulated for extended - release . aswell as the individual weights of the inner and outer layers [0140 ] In other embodiments , the pharmaceutical compo of the polymeric membrane are optimized for achieving sition comprises two active ingredients ( e . g ., two analgesic desired circadian rhythm release profiles for a given active , agents , or a mixture of one analgesic agent and one anti which are predicted based on in vitro / in vivo correlations . insomnia agent or one antimuscarinic agent, or one antidi [0145 ] In other embodiments the formulations comprise a uretic agent, or one spasmolytics , or one a -blockers , or one mixture of immediate - release drug -containing particles 5a - reductase inhibitors , or one PDE5 inhibitor , or one PD without a dissolution rate controlling polymer membrane pathway inhibitor ) formulated for immediate -release , and and delayed -release beads exhibiting , for example , a lag ( 2 ) two active ingredients ( e . g . , two analgesic agents , or a time of 2 - 4 hours following oral administration , thus pro mixture of one analgesic agent and one anti - insomnia agent viding a two - pulse release profile . In yet other embodiments or one antimuscarinic agent, or one antidiuretic agent, or one the formulations comprise a mixture of two types of spasmolytics, or one a - blockers, or one 5a -reductase inhibi delayed -release beads : a first type that exhibits a lag time of tors , or one PDE5 inhibitor, or one PD pathway inhibitor ) 1 - 3 hours and a second type that exhibits a lag time of 4 - 6 formulated for extended -release . hours . 10141 ] In other embodiments , the pharmaceutical compo 10146 ) In some embodiments , the active core is coated sition comprises three active ingredients formulated for with one or more layers of dissolution rate - controlling immediate -release , and ( 2 ) three active ingredients formu polymers to obtain desired release profiles with or without a lated for extended -release . In other embodiments , the phar lag time. An inner layer membrane can largely control the maceutical composition comprises four active ingredients rate of drug release following imbibition of water or body formulated for immediate - release , and (2 ) four active ingre fluids into the core , while the outer layer membrane can dients formulated for extended - release . In these embodi provide for a desired lag time ( the period of no or little drug ments, the active ingredient( s ) in the immediate - release release following imbibition of water or body fluids into the component can be the same as, or different from , the active core ). The inner layer membrane may comprise a water ingredient( s ) in the extended - release component. In some insoluble polymer , or a mixture of water insoluble and other embodiments , the immediate - release component and / water -soluble polymers . or the extended - release component is further coated with a [0147 ] The polymers suitable for the outer membrane , delayed -release coating, such as an enteric coating . which largely controls the lag time of up to 2 , 3 , 4 , 5 or 6 US 2018 /0264013 A1 Sep . 20 , 2018 15 hours may comprise an enteric polymer, as described above , is administered orally or transdermally . In some embodi and a water insoluble polymer at a thickness of 10 to 50 ments , the pharmaceutical composition is administered weight % . The ratio of water insoluble polymer to enteric orally in an orally disintegrating formulation . polymer may vary from 4 : 1 to 1 : 2 , preferably the polymers [0152 ] The appropriate dosage (“ therapeutically effective are present at a ratio of about 1 : 1. The water insoluble amount” ) of the active agent( s ) in the immediate - release polymer typically used is ethylcellulose . component or the extended - release component will depend , [0148 ] Exemplary water insoluble polymers include eth for example , on the severity and course of the condition , the ylcellulose, polyvinyl acetate (Kollicoat SR # OD from mode of administration , the bioavailability of the particular BASF ) , neutral copolymers based on ethyl acrylate and agent( s ) , the age and weight of the patient, the patient' s methylmethacrylate , copolymers of acrylic and methacrylic clinical history and response to the active agent( s ) , discre acid esters with quaternary ammonium groups such as tion of the physician , etc . EUDRAGIT® NE , RS and RS30D , RL or RL30D and the [0153 ] As a general proposition , the therapeutically effec like. Exemplary water - soluble polymers include low tive amount of the active agent( s ) in the immediate -release molecular weight HPMC , HPC ,methylcellulose , polyethyl component, the extended - release component or the delayed ene glycol ( PEG of molecular weight > 3000 ) at a thickness extended -release component is administered in the range of ranging from 1 weight % up to 10 weight % depending on about 100 ug /kg body weight/ day to about 100 mg/ kg body the solubility of the active in water and the solvent or latex weight/ day whether by one or more administrations . In some suspension based coating formulation used . The water embodiments , the range of each active agent administered insoluble polymer to water soluble polymer may typically daily is from about 100 ug /kg body weight/ day to about 50 vary from 95 : 5 to 60 : 40 , preferably from 80 : 20 to 65 :35 . mg /kg body weight /day , 100 ug/ kg body weight/ day to about [0149 ] In some embodiments , the pharmaceutical compo 10 mg/ kg body weight/ day , 100 ug /kg body weight/ day to sition is formulated for systemic administration . In some about 1 mg/ kg body weight/ day , 100 ug/ kg body weight/ day embodiments , the pharmaceutical composition is formulated to about 10 mg/ kg body weight/ day , 500 ug / kg body weight / for oral administration . In some embodiments , the pharma day to about 100 mg/ kg body weight/ day , 500 ug/ kg body ceutical composition is formulated for parenteral adminis weight/ day to about 50 mg/ kg body weight/ day , 500 ug/ kg tration . In some embodiments , the pharmaceutical compo body weight/ day to about 5 mg/ kg body weight/ day , 1 mg/ kg sition is formulated for subcutaneous ( subQ ) administration . body weight/ day to about 100 mg/ kg body weight/ day, 1 In some embodiments , the pharmaceutical composition is mg/ kg body weight/ day to about 50 mg/kg body weight/ day , formulated for intramuscular ( IM ) administration . In some 1 mg/ kg body weight/ day to about 10 mg/ kg body weight/ embodiments , the pharmaceutical composition is formulated day , 5 mg/ kg body weight/ dose to about 100 mg/ kg body for intraperitoneal ( IP ) administration . In some embodi weight /day , 5 mg/ kg body weight/ dose to about 50 mg/ kg ments , the pharmaceutical composition is formulated for body weight /day , 10 mg/kg body weight/ day to about 100 intravenous (IV ) administration . mg/ kg body weight/ day , and 10 mg /kg body weight/ day to [0150 ] In some embodiments , the pharmaceutical compo about 50 mg/ kg body weight/ day . sition is formulated for topical administration . In some [0154 ] The active agent( s ) described herein may be embodiments , the pharmaceutical composition is formulated included in an immediate - release component or an for transdermal administration . In some embodiments , the extended -release component, a delayed - extended -release pharmaceutical composition is formulated for nasal admin component or combinations thereof for daily oral adminis istration . In some embodiments , the pharmaceutical com tration at a single dose or combined dose range of 1 mg to position is formulated for transdermal administration . In 2000 mg, 5 mg to 2000 mg, 10 mg to 2000 mg, 50 mg to some embodiments , the pharmaceutical composition is for 2000 mg, 100 mg to 2000 mg, 200 mg to 2000 mg, 500 mg mulated for buccal administration . In some embodiments , to 2000 mg, 5 mg to 1800 mg, 10 mg to 1600 mg, 50 mg to the pharmaceutical composition is formulated for pulmo 1600 mg, 100 mg to 1500 mg, 150 mg to 1200 mg, 200 mg nary administration . to 1000 mg , 300 mg to 800 mg, 325 mg to 500 mg, 1 mg to [0151 ] The pharmaceutical composition may be adminis 1000 mg, 1 mg to 500 mg, 1 mg to 200 mg, 5 mg to 1000 tered daily or administered on an as needed basis . In certain mg, 5 mg to 500 mg, 5 mg to 200 mg, 10 mg to 1000 mg, embodiments , the pharmaceutical composition is adminis 10 mg to 500 mg, 10 mg to 200 mg, 50 mg to 1000 mg, 50 tered to the subject prior to bedtime. In some embodiments , mg to 500 mg , 50 mg to 200 mg, 250 mg to 1000 mg, 250 the pharmaceutical composition is administered immedi mg to 500 mg, 500 mg to 1000 mg, 500 mg to 2000 mg. As ately before bedtime. In some embodiments , the pharma expected , the dosage will be dependent on the condition , ceutical composition is administered within about two hours size , age and condition of the patient. before bedtime, preferably within about one hour before [0155 ] In some embodiments , the pharmaceutical compo bedtime. In another embodiment, the pharmaceutical com sition comprises a single analgesic agent. In one embodi position is administered about two hours before bedtime. In ment, the single analgesic agent is aspirin . In another a further embodiment , the pharmaceutical composition is embodiment, the single analgesic agent is ibuprofen . In administered at least two hours before bedtime. In another another embodiment, the single analgesic agent is naproxen embodiment, the pharmaceutical composition is adminis sodium . In another embodiment, the single analgesic agent tered about one hour before bedtime. In a further embodi is indomethacin . In another embodiment, the single analge ment, the pharmaceutical composition is administered at sic agent is nabumetone . In another embodiment, the single least one hour before bedtime. In a still further embodiment, analgesic agent is acetaminophen . the pharmaceutical composition is administered less than [0156 ] In some embodiments , the single analgesic agent is one hour before bedtime. In still another embodiment, the given at a daily dose of 1 mg to 2000 mg, 5 mg to 2000 mg, pharmaceutical composition is administered immediately 2020 mg to 2000 mg, 5 mg to 1000 mg, 20 mg to 1000 mg, 50 before bedtime . Preferably , the pharmaceutical composition mg to 500 mg, 100 mg to 500 mg, 250 mg to 500 mg, 250 US 2018 /0264013 A1 Sep . 20 , 2018 16 mg to 1000 mg or 500 mg to 1000 mg. In certain embodi [0159 ] In some embodiment, the pharmaceutical compo ments , the pharmaceutical composition comprises acetyl sition with an immediate - release component and an salicylic acid , ibuprofen , naproxen sodium , indomethancin , extended - release component is formulated into a liquid form nabumetone or acetaminophen as a single analgesic agent for oral administration . Examples of the liquid form formu and the analgesic agent is administered orally at a daily dose lation include, but are not limited to , gels , emulsions and in the range of 5 mg to 2000 mg, 20 mg to 2000 mg, 5 mg particle suspensions . For example , the extended - release to 1000 mg, 20 mg to 1000 mg, 50 mg to 500 mg, 100 mg component may be formulated into a gel form that solidified to 500 mg, 250 mg to 500 mg, 250 mg to 1000 mg or 500 in stomach . In some embodiment, the pharmaceutical com mg to 1000 mg. In some embodiments , a second analgesic position with an immediate -release component and an agent is given at a daily dose of 1 mg to 2000 mg, 5 mg to extended - release component is formulated into a pixie pack 2000 mg, 20 mg to 2000 mg, 5 mg to 1000 mg, 20 mg to of powder that can quickly melt on the tongue . In some 1000 mg, 50 mg to 500 mg, 100 mg to 500 mg, 250 mg to embodiments , the immediate - release component or the 500 mg, 250 mg to 1000 mg or 500 mg to 1000 mg. extended release component or both further comprise one or [0157 ] In other embodiments , the pharmaceutical compo more additional agents selected from the group consisting of sition comprises a pair of analgesic agents . Examples of antimuscarinic agents , spasmolytics and antidiuretic agents . such paired analgesic agents include , but are not limited to , [ 0160 ] In some other embodiments , the pharmaceutical acetylsalicylic acid and ibuprofen , acetylsalicylic acid and composition of the present application further comprises one naproxen sodium , acetylsalicylic acid and nabumetone , ace or more antimuscarinic agents . The daily dose of antimus tylsalicylic acid and acetaminophen , acetylsalicylic acid and carinic agent is in the range of 0 .01 mg to 100 mg, 0 . 1 mg indomethancin , ibuprofen and naproxen sodium , ibuprofen to 100 mg, 1 mg to 100 mg, 10 mg to 100 mg , 0 .01 mg to and nabumetone, ibuprofen and acetaminophen , ibuprofen 25 mg, 0 . 1 mg to 25 mg , 1 mg to 25 mg, 10 mg to 25 mg, and indomethancin , naproxen sodium and nabumetone , 0 .01 mg to 10 mg, 0 . 1 mg to 10 mg, 1 mg to 10 mg, 10 mg naproxen sodium and acetaminophen , naproxen sodium and to 100 mg and 10 mg to 25 mg. indomethancin , nabumetone and acetaminophen , nabume [0161 ] In certain embodiments , the pharmaceutical com tone and indomethancin , and acetaminophen and indometh position comprises an analgesic agent selected from the ancin . The paired analgesic agents are mixed at a weight group consisting of cetylsalicylic acid , ibuprofen , naproxen ratio in the range of 0 . 1 : 1 to 10 : 1 , 0 . 2 : 1 to 5 : 1 or 0 . 3 : 1 to 3 : 1 sodium , nabumetone , acetaminophen and indomethancin , with a combined dose or single dose ( i. e ., the dose for each and an antimuscarinic agent selected from the group con analgesic ) in the range of 5 mg to 2000 mg, 20 mg to 2000 sisting of oxybutynin , solifenacin , darifenacin and atropine . mg , 100 mg to 2000 mg, 200 mg to 2000 mg, 500 mg to [0162 ] In some embodiments , the pharmaceutical compo 2000 mg , 5 mg to 1500 mg, 20 mg to 1500 mg, 100 mg to sition comprises two or more analgesic agents. In some 1500 mg , 200 mg to 1500 mg , 500 mg to 1500 mg , 5 mg to embodiments , the pharmaceutical composition comprises 1000 mg, 20 mg to 1000 mg, 100 mg to 1000 mg, 250 mg one or more analgesic agents and one or more anti - insomnia to 500 mg, 250 mg to 1000 mg , 250 mg to 1500 mg, 500 mg agents . In some embodiments , the pharmaceutical compo to 1000 mg, 500 mg to 1500 mg , 1000 mg to 1500 mg, and sition comprises one or more analgesic agents and one or 1000 mg to 2000 mg. In one embodiment, the paired more antimuscarinic agents . In some embodiments , the analgesic agents are mixed at a weight ratio of 1 : 1 pharmaceutical composition comprises one or more analge 0158 ] In some embodiments , the pharmaceutical compo sic agents and one or more antidiuretic agents . In some sition comprises an immediate - release component and an embodiments , the pharmaceutical composition comprises extended - release component. Each component comprises a one or more analgesic agents and one or more spasmolytics . pair of analgesic agents as described above . In some In some embodiments , the pharmaceutical composition embodiments , the immediate - release component and the comprises one or more analgesic agents and one or more extended - release component comprise different pairs of a -blockers . In some embodiments , the pharmaceutical com analgesic agents . In some embodiments , the immediate position comprises one or more analgesic agents and one or release component and the extended - release component more 5a - reductase inhibitors . In some embodiments , the comprise the samepair of analgesic agents . In some embodi pharmaceutical composition comprises one or more analge ments, the immediate -release component and the extended sic agents and one or more phosphodiesterase type 5 (PDE5 ) release component each comprises acetaminophen and ibu inhibitors . In some embodiments, the pharmaceutical com profen . In some embodiments , the immediate - release position comprises one or more analgesic agents and one or component and the extended - release component each con more PD pathway inhibitors . sists of acetaminophen and ibuprofen . In some embodi [0163 ] The pharmaceutical composition may be formu ments , the extended -release component is formulated for lated into a tablet, capsule , dragee , powder , granulate , liquid , extended release over a period of 0 . 5 - 24 , 2 - 6 , 6 - 10 , 10 - 14 or gel or emulsion form . Said liquid , gel or emulsion may be 14 - 18 hours. In some embodiments, the extended -release ingested by the subject in naked form or contained within a component is formulated for extended release over a period capsule . of about 8 hours . In some embodiments , the extended [0164 ] In certain embodiments , the analgesic agent is release component is coated with a delayed -release coating . selected from the group consisting of salicylates , aspirin , In some embodiments , the delayed -release coating delays salicylic acid , methyl salicylate , diflunisal, salsalate , olsala the release of the extended - release component for a period zine , sulfasalazine , para -aminophenol derivatives, aceta of 0 . 1 - 12 , 1 -4 , 4 - 8 or 8 -12 hours . In some embodiments , the nilide, acetaminophen , phenacetin , fenamates, mefenamic delayed -release coating is an enteric coating . In some acid , meclofenamate, sodium meclofenamate , heteroaryl embodiment, the pharmaceutical composition with an acetic acid derivatives , tolmetin , ketorolac , diclofenac , pro immediate - release component and an extended -release com pionic acid derivatives, ibuprofen , naproxen sodium , ponent is formulated into an orally disintegrating tablet. naproxen , fenoprofen , ketoprofen , flurbiprofen , oxaprozin ; US 2018 /0264013 A1 Sep . 20 , 2018 17 enolic acids , oxicam derivatives , piroxicam , meloxicam , alternatively to prevent the development of drug resistance . tenoxicam , ampiroxicam , droxicam , pivoxicam , pyrazolon In one embodiment, the method comprises administering a derivatives , phenylbutazone, oxyphenbutazone, antipyrine , first analgesic agent for a first period of time and then aminopyrine, dipyrone , coxibs, celecoxib , rofecoxib , nabu administering a second analgesic agent for a second period metone , apazone, nimesulide, indomethacin , sulindac , etod of time . In another embodiment, the method further com olac , diflunisal and isobutylphenyl propionic acid . The anti prises administering a third analgesic agent for a third period muscarinic agent is selected from the group consisting of of time. The first , second and third analgesic agents are oxybutynin , solifenacin , darifenacin and atropine . different from each other and at least one of which is [0165 ] In some embodiments , the pharmaceutical compo formulated for extended - release or delayed , extended - re sition comprises a single analgesic and a single agent lease . In one embodiment, the first analgesic agent is acet selected from the group consisting of anti - insomnia agents , aminophen , the second analgesic agent is ibuprofen and the antimuscarinic agents , antidiuretic agents , spasmolytics , third analgesic agent is naproxen sodium . The length of each a -blockers , 5a - reductase inhibitors , phosphodiesterase type period may vary depending on the subject' s response to each 5 ( PDE5 ) inhibitors and prostaglandin (PD ) pathway inhibi analgesic agent. In some embodiments , each period lasts tors. In one embodiment, the single analgesic agent is from one week to one year. In another embodiment, the first , aspirin . In another embodiment , the single analgesic agent is second and third analgesic are all formulated for extended ibuprofen . In another embodiment, the single analgesic release or delayed , extended - release . agent is naproxen sodium . In another embodiment, the [0171 ] In some embodiments , the pharmaceutical compo single analgesic agent is indomethacin . In another embodi sition of the present application comprises a pharmaceuti ment, the single analgesic agent is nabumetone . In another cally acceptable carrier. embodiment, the single analgesic agent is acetaminophen . [0172 ] As used herein , " pharmaceutically acceptable car The analgesic agent and anti- muscarinic agent may be given rier ” includes any and all solvents , dispersion media , coat at doses in the ranges described above . ings, antibacterial and agents , isotonic and [0166 ] In some embodiments , the pharmaceutical compo absorption delaying agents , sweeteners and the like . The sition comprises a pair of analgesics and a single agent pharmaceutically acceptable carriers may be prepared from selected from the group consisting of anti - insomnia agents , a wide range of materials including , but not limited to , antimuscarinic agents , antidiuretic agents , spasmolytics , flavoring agents, sweetening agents and miscellaneous a -blockers , 5a - reductase inhibitors , phosphodiesterase type materials such as buffers and absorbents that may be needed 5 ( PDE5 ) inhibitors and prostaglandin ( PD ) pathway inhibi in order to prepare a particular therapeutic composition . The tors. In some embodiments , the pair of analgesics are use of such media and agents with pharmaceutically active acetaminophen and ibuprofen . The analgesics may be given substances is well known in the art . Except insofar as any at doses in the ranges described above . In some embodi conventional media or agent is incompatible with the active ments , the single agent is an anti - insomnia agent . ingredient, its use in the therapeutic compositions is con [ 0167 ] Another aspect of the present application relates to templated . a method for treating sleep disorder by administering to a [0173 ] In some embodiments , the pharmaceutical compo person in need thereof an effective an effective mount of a sition comprises a first component having an immediate pharmaceutical composition comprising one or more anal release subcomponent and an extended -release subcompo gesics , and a composition comprising an anti- insomnia nent, wherein the first component is formulated to release agent. In some embodiments , the analgesic - containing com the subcomponents immediately after administration , and a position and the anti - insomnia agent containing composition second component comprising an immediate - release sub is administered at the same time. In some embodiments , the component and an extended -release subcomponent, wherein analgesic - containing composition is administered first, fol the second component is formulated for a delayed - release of lowed by the administration of the anti- insomnia agent the subcomponents . In some embodiments , at least one of containing composition . In some embodiments , the anti the subcomponents in the first component or the second insomnia agent - containing composition is administered first , component comprises an active ingredient comprising one followed by the administration of the analgesic agent con or more analgesic agents . In some embodiments , the one or taining composition . more analgesic agents are selected from the group consisting [ 0168 ] In some embodiments , the analgesic - containing of aspirin , ibuprofen , naproxen , naproxen sodium , indo composition comprises acetaminophen . In some embodi methacin , nabumetone , and acetaminophen . In some ments , the analgesic - containing composition comprises ibu embodiments , the one or more analgesic agents comprise profen . In some embodiments , the analgesic -containing acetaminophen and ibuprofen . In some embodiments , the composition comprises both acetaminophen and ibuprofen . one or more analgesic agents consist of acetaminophen and [ 0169 ] Another aspect of the present application relates to ibuprofen . a method for treating sleep disorder by administering to a 101741 In some embodiments , the immediate - release sub person in need thereof an effective mount of a pharmaceu component and the extended -release subcomponent in the tical composition comprising one or more analgesics , and a first component each comprises an active ingredient com composition comprising an agent selected from the group prising one or more analgesic agents . In other embodiments , consisting of antimuscarinic agents , antidiuretic agents , the immediate - release subcomponent and the extended - re spasmolytics, a -blockers , 5a - reductase inhibitors , phos lease subcomponent in the second component each com phodiesterase type 5 ( PDE5) inhibitors and prostaglandin prises an active ingredient comprising one or more analgesic ( PD ) pathway inhibitors . agents . In some embodiments , the one or more analgesic [0170 ] Another aspect of the present application relates to agents are selected from the group consisting of aspirin , a method for treating sleep disorders by administering to a ibuprofen , naproxen , naproxen sodium , indomethacin , nabu subject in need thereof, two or more analgesic agents metone , and acetaminophen . In some embodiments , the one US 2018 /0264013 A1 Sep . 20 , 2018 18 or more analgesic agents comprise acetaminophen and ibu dient in the immediate - release subcomponent of the second profen . In some embodiments , the one or more analgesic component comprise different analgesic agents . agents consist of acetaminophen and ibuprofen . In yet other [0181 ] In other embodiments , the pharmaceutical compo embodiments , each of the subcomponents in the first com sition comprises a first component comprising an immedi ponent or the second component comprises an active ingre ate - release subcomponent, wherein the immediate - release dient comprising one or more analgesic agents. In some subcomponent comprises an active ingredient comprising embodiments, the one or more analgesic agents are selected one or two analgesic agents, such as acetaminophen , ibu from the group consisting of aspirin , ibuprofen , naproxen , profen or a combination of acetaminophen and ibuprofen , in naproxen sodium , indomethacin , nabumetone , and acet an amount of 5 - 2000 mg, wherein the first component is aminophen . In some embodiments , each of the subcompo formulated to release its subcomponent immediately after nents in the first component or the second component oral administration , and a second component comprising an comprises acetaminophen and ibuprofen . In some embodi- immediate -release subcomponent and an extended -release ments, each of the subcomponents in the first component or subcomponent, wherein the second component is formulated the second component consist of acetaminophen and ibu to release its subcomponent after gastric emptying , wherein profen . the immediate - release subcomponent and the extended - re [ 0175 ] In some embodiments , the second component is lease subcomponent in the second component each com coated with an enteric coating . In some embodiments , the prises an active ingredients comprising one or more anal second component is formulated to release the subcompo gesic agents . In some embodiments , the one or more nents after a lag time of 2 - 6 hours , 2 - 5 hours , 2 - 4 hours , 2 - 3 analgesic agents are selected from the group consisting of hours, 3 -6 hours, 3 - 5 hours, 3 - 4 hours , 4 - 6 hours , 4 - 5 hours aspirin , ibuprofen , naproxen , naproxen sodium , indometha or 5 - 6 hours following oral administration . cin , nabumetone , and acetaminophen . 10176 ]. In some embodiments , the extended - release sub 10182 ]. In some embodiments , the second component is component in the first component is formulated to release its formulated to release the subcomponents after a lag time of active ingredient over a time interval of about 2 - 10 , 2 - 9 , 2 - 8 , 2 - 6 hours , 2 - 5 hours, 2 - 4 hours , 2 - 3 hours, 3 - 6 hours , 3 - 5 2 - 7, 2 -6 , 2 - 5 or 2 -4 hours . hours, 3 - 4 hours, 4 - 6 hours, 4 - 5 hours or 5 - 6 hours following (0177 ] In some embodiments , the extended -release sub oral administration . component in the second component is formulated to release 10183 ]. In some embodiments , the active ingredient in the its active ingredient over a time interval of about 2 - 10 , 2 - 9 , immediate - release subcomponent and the extended - release 2 - 8 , 2 - 7 , 2 - 6 , 2 - 5 or 2 - 4 hours. subcomponent of the second component comprises one or [0178 ] In some embodiments , the active ingredient in the more analgesic agents . In some embodiments , the first immediate - release subcomponent and the extended -release component further comprises an extended - release subcom subcomponent in the first component further comprises an ponent, wherein the extended -release subcomponent com anti - insomnia agent. In some embodiments , the active ingre prises an active ingredient comprising one or more analgesic dient in the immediate - release subcomponent and the agents . In some embodiments , the one or more analgesic extended - release subcomponent in the second component agents are selected from the group consisting of aspirin , further comprises an anti- insomnia agent. In some embodi ibuprofen , naproxen , naproxen sodium , indomethacin , nabu ments, the active ingredient in the immediate - release sub metone , and acetaminophen . component and the extended - release subcomponent in both [0184 ] In some embodiments , at least one of the active the first and the second component further comprises an ingredient in the immediate- release subcomponent and the anti - insomnia agent. extended -release subcomponent of the first and the second [ 0179 ] In some embodiments, the immediate - release sub components further comprises an agent selected from the component and the extended -release subcomponent in the group consisting of anti - insomnia agents , antimuscarinic first component each comprises one or two analgesic agents, agents , antidiuretic agents , spasmolytics , a -blockers , 5a - re such as acetaminophen , ibuprofen or a combination of ductase inhibitors , phosphodiesterase type 5 (PDE5 ) inhibi acetaminophen and ibuprofen , in an amount of 5 - 2000 mg. tors and prostaglandin (PD ) pathway inhibitors . In some In some embodiments , the immediate -release subcomponent embodiments , at least one of the active ingredient in the and the extended - release subcomponent in the second com immediate - release subcomponent and the extended - release ponent each comprises one or two analgesic agents , such as subcomponent of the first and the second components fur acetaminophen , ibuprofen or a combination of acetamino ther comprises an anti - insomnia agent. phen and ibuprofen , in an amount of 5 - 2000 mg . In some 10185 ) In some embodiments , the active ingredient in the embodiments , the active ingredient in the immediate -release immediate -release subcomponent and the extended - release subcomponent and the extended - release subcomponent in subcomponent of the first component further comprises an both the first and the second component each comprises one agent selected from the group consisting of anti - insomnia or two analgesic agents , such as acetaminophen , ibuprofen agents , antimuscarinic agents , antidiuretic agents , spasmo or a combination of acetaminophen and ibuprofen , in an lytics , a -blockers , 5a - reductase inhibitors, phosphodies amount of 5 - 2000 mg . terase type 5 (PDE5 ) inhibitors and prostaglandin (PD ) [0180 ] In some embodiments , the active ingredient in the pathway inhibitors . immediate -release subcomponent of the first component and [0186 ] In some embodiments , the active ingredient in the the active ingredient in the immediate -release subcompo immediate - release subcomponent and the extended - release nent of the second component both comprise one or two subcomponent of the second component further comprises analgesic agents , such as acetaminophen , ibuprofen or a an agent selected from the group consisting of antimuscar combination of acetaminophen and ibuprofen . In some inic agents, antidiuretic agents and spasmolytics. embodiments , the active ingredient in the immediate -release [ 0187 ] In other embodiments , the pharmaceutical compo subcomponent of the first component and the active ingre sition comprises a first component comprising an immedi US 2018 /0264013 A1 Sep . 20 , 2018 ate - release subcomponent and an extended - release subcom - of analgesic agents is the same as the second pair of ponent, wherein the first component is formulated to release analgesic agents . In one embodiment , the first pair of the subcomponents immediately after administration , and a analgesic agents and the second pair of analgesic agents are second component comprising an immediate -release sub - both acetaminophen and ibuprofen . component and an extended -release subcomponent, wherein [0193 ] For example , the extended - release component may the second component is formulated for a delayed - release of be formulated into a gel form that solidified in stomach . In the subcomponents , wherein the immediate- release subcom some embodiment, the pharmaceutical composition with an ponent and the extended - release subcomponent in the first immediate - release component and an extended -release com component each comprises an active ingredient comprising ponent is formulated into a pixie pack of powder that can one or more analgesic agents , and wherein the immediate quickly melt on the tongue . In some embodiments , the release subcomponent and the extended - release subcompo pharmaceutical composition with an immediate - release nent in the second component each comprises an active component and an extended - release component is formu ingredient comprising one or more analgesic agents , lated into an orally disintegrating tablet using loose com wherein the pharmaceutical composition reduces the fre pression tableting . In loose compression , orally disintegrat quency of urination in patients in need thereof . In some ing formulation is compressed at much lower forces ( 4 - 20 embodiments , the one or more analgesic agents are selected KN ) than traditional tablets. In some embodiments , the orally from the group consisting of aspirin , ibuprofen , naproxen , disintegrating formulation contains some form of sugar, naproxen sodium , indomethacin , nabumetone , and acet such as mannitol, to improve mouth feel . In some embodi aminophen . ments , the orally disintegrating tablet is produced using [0188 ] In some embodiments , the fourth active ingredient lyophilized orally disintegrating formulation . is kept in a compartment partially or completely separated [0194 ] The present invention is further illustrated by the from the third active ingredient. In other embodiments , thehe following example which should not be construed as limit second mixture is formed by keeping the fourth active ing . The contents of all references , patents and published ingredient in a compartment partially or completely sepa patent applications cited throughout this application are rated from the third active ingredient. incorporated herein by reference . [0189 ] Another aspect of the present application relates to a method for manufacturing a pharmaceutical composition Example 1 : Inhibition of the Urge to Urinate for reducing the frequency of urination . The method com prises the steps of forming a core structure comprising a first [0195 ] Twenty volunteer subjects , both male and female pair of analgesic agents formulated for extended - release and were enrolled , each of which experienced premature urge or coating the core structure with a coating layer comprising a desire to urinate , interfering with their ability to sleep for a second pair of analgesics , wherein the second pair of anal sufficient period of time to feel adequately rested . Each gesics is formulated for immediate release . subject ingested 400 - 800 mg of ibuprofen as a single dose [0190 ] In some embodiments, the core structure is first prior to bedtime . At least 14 subjects reported that they were coated with a delayed - release coating and then coated with able to rest better because they were not being awakened as a coating layer comprising a second pair of analgesics , frequently by the urge to urinate . wherein the second pair of analgesics is formulated for [0196 ] Several subjects reported that after several weeks immediate release . of nightly use of ibuprofen , the benefit of less frequent urges [0191 ] In some embodiments , the method comprises the to urinate was no longer being realized . However, all of steps of forming a first mixture comprising a first pair of these subjects further reported the return of the benefit after analgesic agents formulated for extended -release , forming a several days of abstaining from taking the dosages. second mixture comprising a second pair of analgesic agents Example 2 : Effect of Analgesic Agents , Botulinum formulated for immediate - release , and combining the first Neurotoxin and Antimuscarinic Agents on mixture and the second mixture to form a final mixture . In Macrophage Responses to Inflammatory and some embodiments , the first mixture , the second mixture and the finalmixture are mixtures of solid materials . In some Non -Inflammatory Stimuli embodiments , the final mixture is in powder or granulate Experimental Design form . In some embodiments , the method further comprises the step of pressing the final mixture into a tablet form . In [0197 ] This study is designed to determine the dose and in some embodiments , the final mixture is in a liquid , gel or vitro efficacy of analgesics and antimuscarinic agents in emulsion form . controlling macrophage response to inflammatory and non [0192 ] Examples of paired analgesic agents include, but inflammatory stimuli mediated by COX2 and prostaglandins are not limited to , acetylsalicylic acid and ibuprofen , ace (PGE , PGH , etc . ) . It establishes baseline (dose and kinetic ) tylsalicylic acid and naproxen sodium , acetylsalicylic acid responses to inflammatory and non - inflammatory effectors and nabumetone , acetylsalicylic acid and acetaminophen , in bladder cells . Briefly , cultured cells are exposed to anal acetylsalicylic acid and indomethancin , ibuprofen and gesic agents and /or antimuscarinic agents in the absence or naproxen sodium , ibuprofen and nabumetone , ibuprofen and presence of various effectors . acetaminophen , ibuprofen and indomethancin , naproxen [0198 ] The effectors include : lipopolysaccharide (LPS ) , sodium and nabumetone , naproxen sodium and acetamino an inflammatory agent and Cox2 inducer, as inflammatory phen , naproxen sodium and indomethancin , nabumetone stimuli; carbachol or acetylcholine , a stimulator of smooth and acetaminophen , nabumetone and indomethancin , and muscle contraction , as non - inflammatory stimuli ; botulinum acetaminophen and indomethancin . In some embodiments , neurotoxin A , a known inhibitor of acetylcholine release , as the first pair of analgesic agents is different from the second positive control; and arachidonic acid (AA ), gamma lino pair of analgesic agents . In other embodiments , the first pair lenic acid ( DGLA ) or eicosapentaenoic acid (EPA ) as pre US 2018 /0264013 A1 Sep . 20 , 2018

cursors of prostaglandins, which are produced following the lipopolysaccharide (LPS ), which is an effector of inflam sequential oxidation of AA , DGLA or EPA inside the cell by matory stimuli to macrophage cells , ( 3 ) various concentra cyclooxygenases (COX1 and COX2 ) and terminal prosta tions of carbachol or acetylcholine , which are effectors of glandin synthases. non - inflammatory stimuli, ( 4 ) analgesic and LPS or (5 ) [0199 ] The analgesic agents include: Salicylates such as analgesic and carbachol or acetylcholine. Briefly , the anal aspirin , iso -butyl - propanoic -phenolic acid derivative ( ibu gesics were dissolved in FBS - free culture medium ( i. e profen ) such as Advil, Motrin , Nuprin , and Medipren , RPMI 1640 supplemented with 15 mM HEPES , 2 mM naproxen sodium such as Aleve , Anaprox , Antalgin , Femi L - glutamine , 100 U /ml penicillin , and 100 ug/ ml of strep nax Ultra , Flanax , Inza , Midol Extended Relief, Nalgesin , tomycin ), and diluted to desired concentrations by serial Naposin , Naprelan , Naprogesic , Naprosyn , Naprosyn sus dilution with the same medium . For cells treated with pension , EC -Naprosyn , Narocin , Proxen , Synflex and Xeno analgesic in the absence of LPS , 50 ul of analgesic solution bid , acetic acid derivative such as indomethacin ( Indocin ) , and 50 ul of FBS - free culture medium were added to each 1 - naphthaleneacetic acid derivative such as nabumetone or well. For cells treated with analgesic in the presence of LPS , relafen , N - acetyl- para - aminophenol (APAP ) derivative such 50 ul of analgesic solution and 50 ul of LPS ( from Salmo as acetaminophen or paracetamol ( Tylenol) and Celecoxib . nella typhimurium ) in FBS - free culture medium were added [ 0200 ] The antimuscarinic agents include : oxybutynin , to each well . All conditions were tested in duplicates . solifenacin , darifenacin and atropine . [ 0217 ] After 24 or 48 hours of culture, 150 ul of culture [ 0201) Macrophages are subjected to short term ( 1 - 2 hrs ) supernatants were collected , spun down for 2 min at 8 ,000 or long term (24 - 48 hrs ) stimulation of with : rpm at 4° C . to remove cells and debris and stored at - 70° [ 0202 ] 1 ) Each analgesic agent alone at various doses . C . for analysis of cytokine responses by ELISA . The cells [0203 ] ( 2 ) Each analgesic agent at various doses in the were collected and washed by centrifugation (5 min at 1 , 500 presence of LPS . rpm at 4° C .) in 500 ul of Phosphate buffer (PBS ) . Half of [0204 ] (3 ) Each analgesic agent at various doses in the the cells were then snap frozen in liquid and stored presence of carbachol or acetylcholine . at - 70° C . The remaining cells were stained with fluorescent [ 0205 ] ( 4 ) Each analgesic agent at various doses in the monoclonal antibodies and analyzed by flow cytometry. presence of AA , DGLA , or EPA . [ 0206 ] ( 5 ) Botulinum neurotoxin A alone at various doses . Flow Cytometry Analysis of Co - Stimulatory Molecule [0207 ] (6 ) Botulinum neurotoxin A at various doses in the Expression presence of LPS . (0208 ) ( 7 ) Botulinum neurotoxin A at various doses in the [0218 ] For flow cytometry analysis , macrophages were presence of carbachol or acetylcholine . diluted in 100 ul of FACS buffer (phosphate buffered saline 50209 ( 8 ) Botulinum neurotoxin A at various doses in the ( PBS ) with 2 % bovine serum albumin (BSA ) and 0 .01 % presence of AA , DGLA , or EPA . NaNz) and stained 30 min at 4° C . by addition of FITC [ 0210 ] ( 9 ) Each antimuscarinic agent alone at various conjugated anti - CD40 , PE - conjugated anti -CD80 , PE -con doses . jugated anti- CD86 antibody, anti MHC class II ( I - AC ) PE [0211 ] ( 10 ) Each antimuscarinic agent at various doses in (BD Bioscience ) . Cells were then washed by centrifugation the presence of LPS . ( 5 min at 1, 500 rpm at 4° C .) in 300 ul of FACS buffer. After ( 0212 ) ( 11 ) Each antimuscarinic agent at various doses in a second wash , cells were re- suspended in 200 ul of FACS the presence of carbachol or acetylcholine. buffer and the percentage of cells expressing a given marker [ 0213] ( 12 ) Each antimuscarinic agent at various doses in ( single positive ), or a combination of markers ( double the presence of AA , DGLA , or EPA . positive ) were analyzed with the aid of an Accuri C6 flow [0214 ] The cells are then analyzed for the release of PGH , cytometer (BD Biosciences ) . PGE , PGE2, Prostacydin , Thromboxane , IL -1B , IL -6 , TNF a , the COX2 activity, the production of cAMP and CGMP, Analysis of Cytokine Responses by ELISA the production of IL - 1B , IL - 6 , TNF - a and COX2 mRNA , [0219 ] Culture supernatants were subjected to cytokine and surface expression of CD80 , CD86 and MEW class II specific ELISA to determine IL - 1B , IL - 6 and TNF - a molecules . responses in cultures of macrophages treated with analgesic , LPS alone or a combination of LPS and analgesic . The Materials and Methods assays were performed on Nunc MaxiSorp Immunoplates (Nunc ) coated overnight with 100 ul of anti -mouse IL - 6 , Macrophage Cells TNF - a mAbs (BD Biosciences ) or IL - 13 mAb ( R & D Sys [0215 ] Murine RAW264 .7 or 1774 macrophage cells (ob tems) in 0 . 1 M sodium bicarbonate buffer ( pH 9 . 5 ) . After tained from ATCC ) were used in this study. Cells were two washes with PBS ( 200 ul per well ), 200 ul of PBS 3 % maintained in a culture medium containing RPMI 1640 BSA were added in each well (blocking ) and the plates supplemented with 10 % fetal bovine serum (FBS ) , 15 mM incubated for 2 hours at room temperature . Plates were HEPES , 2 mM L - glutamine, 100 U /ml penicillin , and 100 washed again two times by addition of 200 ul per well, 100 ug /ml of streptomycin . Cells were cultured at 37° C . in a 5 % ul of cytokine standards and serial dilutions of culture CO , atmosphere and split (passages ) once a week . supernatants were added in duplicate and the plates were In Vitro Treatment of Macrophage Cells with Analgesics incubated overnight at 4° C . Finally , the plates were washed [ 0216 RAW264 . 7 macrophage cells were seeded in twice and incubated with 100 ul of secondary biotinylated 96 -well plates at a cell density of 1 . 5x10 cells per well in anti- mouse IL - 6 , TNFa mAbs (BD Biosciences) or IL - 1B 100 ul of the culture medium . The cells were treated with ( 1 ) ( R & D Systems) followed by peroxidase - labelled goat anti various concentrations of analgesic ( acetaminophen , aspirin , biotin mAb ( Vector Laboratories ) . The colorimetric reaction ibuprofen or naproxen ), ( 2 ) various concentrations of was developed by the addition of 2 ,2 '- azino -bis (3 ) -ethyl US 2018 /0264013 A1 Sep . 20 , 2018 21 benzylthiazoline - 6 - sulfonic acid ( ABTS ) substrate and signals and thus, was evaluated to determine functional H , O , (Sigma ) and the absorbance measured at 415 nm with consequences of inhibition of COX2 . a Victor® V multilabel plate reader ( PerkinElmer ) . [0222 ] As shown in Table 2 , acetaminophen , aspirin , ibu Determination of COX2 Activity and the Production of profen and naproxen inhibit basal expression of co - stimu CAMP and CGMP latory molecules CD40 and CD80 by macrophages at all the [ 0220 ] The COX2 activity in the cultured macrophages is tested doses ( i. e ., 5x10 nM , 5x104 nM , 5x10 nM , 5x102 determined by sequential competitive ELISA (R & D Sys nM , 50 nM and 5 nM ), except for the highest dose (i . e ., tems ) . The production of CAMP and CGMP is determined by 5x100 nM ) , which appears to enhance , rather than inhibit , the cAMP assay and cGMP assay. These assays are per expression of the co - stimulatory molecules. As shown in formed routinely in the art. FIGS . 1A and 1B , such inhibitory effect on CD40 and CD50 expression was observed at analgesic doses as low as 0 . 05 Results nM ( i. e ., 0 . 00005 This finding supports the notion that a [0221 ] Table 1 summarizes the experiments performed controlled release of small doses of analgesic may be with Raw 264 macrophage cell line and main findings in preferable to acute delivery of large doses. The experiment terms of the effects of analgesics on cell surface expression also revealed that acetaminophen , aspirin , ibuprofen and of costimulatory molecules CD40 and CD80 . Expression of naproxen have a similar inhibitory effect on LPS induced these molecules is stimulated by COX2 and inflammatory expression of CD40 and CD80 . TABLE 1 Summary of experiments

LPS Salmonella Control typhimurium Acetaminophen Aspirin Ibuprophen Naproxen

TESTS

X NA Dose responses (0 , 5 , 50 , 1000 ) ng/ mL W Dose responses ( 0 , 5 , 50 , 500 , 5 x 103, 5 x 104 , 5 x 10 %, 5 x 106) NM A X ( 5 ng/ mL ) Dose responses X ( 50 ng/ mL (0 , 5 , 50 , 500 , 5 x 103, 5 x 104 , 5 x 105 , 5 x 106 ) nM X ( 1000 ng/ mL ) ANALYSIS Characterization of activation / stimulatory status: Flow cytometry analysis of CD40 , CD80 , CD86 and MHC class II To Mediators of inflammatory responses : ELISA analysis of IL - 1B , IL - 6 , TNF - a TABLE 2 Summary of main findings Negative LPS 5 Effectors % Positive Control ng/ ml 5 x 106 5 x 105 5 x 104 5 x 103 500 50 5 Dose analgesic (nM ) CD40 + CD80 + 20 . 6 77 . 8 Acetaminophen CD40 + CD80 + 63 18 1212 9. . 8 8 . 33 9 . 5 7 . 5 Aspirin CD40 + CD80 + 44 11 10 . 3 8 . 3 8 10 . 5 7 . 5 Ibuprophen CD40 + CD80 + ND * 6 . 4 7. 7 7 . 9 6 . 0 4 . 9 5 . 8 Naproxen CD40 + CD80 + 37 9 .6 7 .7 6 .9 7 . 2 6 . 8 5 . 2 Analgesic plus LPS Acetaminophen CD40 + CD80 + 95 . 1 82 . 7 72. 4 68 . 8 66 . 8 66 . 2 62 . 1 Aspirin CD40 + CD80 + 84 . 5 80 78 . 7 74 . 7 75 . 8 70 . 1 65 . 7 Ibuprophen CD40 + CD80 + ND 67 77 . 9 72. 9 71 . 1 63. 7 60 . 3 Naproxen CD40 + CD80 + 66 . 0 74 . 1 77 . 1 71. 0 68 . 8 72 73 * ND : not done (toxicity ) US 2018 /0264013 A1 Sep . 20 , 2018

[0223 ] Table 3 summarizes the results of several studies [0237 ] ( 11) Each antimuscarinic agent at various doses in that measured serum levels of analgesic after oral therapeu the presence of carbachol or acetylcholine . tic doses in adult humans. As shown in Table 3 , the maxi [0238 ] ( 12 ) Each antimuscarinic agent at various doses in mum serum levels of analgesic after an oral therapeutic dose the presence of AA , DGLA , or EPA . are in the range of 104 to 10 nM . Therefore , the doses of [0239 ] The cells are then analyzed for the release of PGHz, analgesic tested in vitro in Table 2 cover the range of PGE , PGE2, Prostacydin , Thromboxane , IL - 1B , IL -6 , TNF concentrations achievable in vivo in humans . a , the COX2 activity , the production of CAMP and CGMP, TABLE 3 Serum levels of analgesic in human blood after oral therapeutic doses Maximum serum levels after oral Molecular therapeutic doses Analgesic drug weight mg/ L nM References Acetaminophen 151. 16 11- 18 7 . 2 x 104 . BMC Clinical Pharmacology . 2010 , 10 : 10 ( Tylenol ) 1 . 19 x 105 Anaesth Intensive Care . 2011 , 39 : 242 Aspirin 181. 66 30 - 100 1. 65 x 105 - Disposition of Toxic Drugs and Chemicals in ( Acetylsalicylic 5 . 5 x 105 Man , 8th Edition , Biomedical Public , Foster acid ) City , CA , 2008 , pp . 22- 25 J Lab Clin Med . 1984 June ; 103 : 869 Ibuprofen 206 .29 24 - 32 1 .16 x 105- BMC Clinical Pharmacology 2010 , 10 : 10 (Advil , Motrin ) 1 .55 x 105 J Clin Pharmacol. 2001 , 41 : 330 Naproxen 230 . 26 Up to Up to J Clin Pharmacol. 2001 , 41 : 330 ( Aleve ) 60 2 .6 x 105

Example 3 : Effect of Analgesic Agents , Botulinum the production of IL - 1B , IL -6 , TNF -a and COX2 mRNA , Neurotoxin and Antimuscarinic Agents on Mouse and surface expression of CD80 , CD86 and MEW class II Bladder Smooth Muscle Cell Responses to molecules . Inflammatory and Non - Inflammatory Stimuli Materials and Methods Experimental Design Isolation and Purification of Mouse Bladder Cells [0240 ] Bladder cells were removed from euthanized ani [ 0224 ] This study is designed to characterize how the mals C57BL /6 mice ( 8 - 12 weeks old ) and cells were isolated optimal doses of analgesic determined in Example 2 affect by enzymatic digestion followed by purification on a Percoll bladder smooth muscle cells in cell culture or tissue cultures, gradient. Briefly , bladders from 10 mice were minced with and to address whether different classes of analgesics can scissors to fine slurry in 10 ml of digestion buffer (RPMI synergize to more efficiently inhibit COX2 and PGE2 1640 , 2 % fetal bovine serum , 0 . 5 mg/ ml collagenase , 30 responses . ug/ ml DNase ). Bladder slurries were enzymatically digested for 30 minutes at 37° C . Undigested fragments were further [0225 ] The effectors , analgesic agents and antimuscarinic dispersed through a cell- trainer . The cell suspension was agents are described in Example 2 . pelleted and added to a discontinue 20 % , 40 % and 75 % [0226 ] Primary culture of mouse bladder smooth muscle Percoll gradient for purification on mononuclear cells . Each cells are subjected to short term ( 1 - 2 hrs ) or long term ( 24 - 48 experiment used 50 -60 bladders. hrs ) stimulation of with : 0241 ) After washes in RPMI 1640 , bladder cells were [ 0227 ] ( 1 ) Each analgesic agent alone at various doses . resuspended RPMI 1640 supplemented with 10 % fetal [ 0228 ] (2 ) Each analgesic agent at various doses in the bovine serum , 15 mM HEPES , 2 mM L - glutamine , 100 presence of LPS . U /ml penicillin , and 100 ug/ ml of streptomycin and seeded [ 02291 ( 3 ) Each analgesic agent at various doses in the in clear - bottom black 96 - well cell culture microculture presence of carbachol or acetylcholine . plates at a cell density of 3x104 cells per well in 100 ul . Cells were cultured at 37° C . in a 5 % CO2 atmosphere . [0230 ] (4 ) Each analgesic agent at various doses in the In Vitro Treatment of Cells with Analgesics presence of AA , DGLA , or EPA . [0242 ] Bladder cells were treated with analgesic solutions (0231 ] ( 5 ) Botulinum neurotoxin A alone at various doses . (50 ul/ well ) either alone or together with carbachol ( 10 0232 ( 6 ) Botulinum neurotoxin A at various doses in the Molar, 50 ul/ well ) , as an example of non - inflammatory presence of LPS . stimuli , or lipopolysaccharide (LPS ) of Salmonella typhimu 10233 ] (7 ) Botulinum neurotoxin A at various doses in the rium ( 1 ug /ml , 50 ul/well ) , as an example of non - inflam presence of carbachol or acetylcholine . matory stimuli. When no other effectors were added to the cells , 50 ul of RPMI 1640 without fetal bovine serum were [ 02341 ( 8 ) Botulinum neurotoxin A at various doses in the added to the wells to adjust the final volume to 200 ul. presence of AA , DGLA , or EPA . [0243 ] After 24 hours of culture , 150 ul of culture super [0235 ] ( 9 ) Each antimuscarinic agent alone at various natants were collected , spun down for 2 min at 8 , 000 rpm at doses. 4° C . to remove cells and debris and stored at - 70° C . for [ 0236 ] ( 10 ) Each antimuscarinic agent at various doses in analysis of Prostaglandin E2 ( PGE ) responses by ELISA . the presence of LPS . Cells were fixed , permeabilized and blocked for detection of US 2018 /0264013 A1 Sep . 20 , 2018 22

Cyclooxygenase - 2 ( COX2 ) using a fluorogenic substrate . In suppress the effect of LPS on COX2 levels . The suppressive selected experiment cells were stimulated 12 hours in vitro effect of the analgesic was seen when these drugs were for analysis of COX2 responses tested at either 5 uM or 50 °M ( Table 4 ) . Analysis of COX2 Responses TABLE 4 [0244 ] COX2 responses were analyzed by a Cell -Based COX2 expression by mouse bladder cells after in ELISA using Human /mouse total COX2 immunoassay vitro stimulation and treatment with analgesic ( R & D Systems) , following the instructions of the manufac turer . Briefly , after cells fixation and permeabilization , a Total COX2 levels mouse anti - total COX2 and a rabbit anti - totalGAPDH were Stimuli Analgesic (Normalized RFUS) added to the wells of the clear- bottom black 96 -well cell None None 158 + 18 culture microculture plates . After incubation and washes , an Carbachol (mm ) None 149 = 21 LPS ( 1 ug /ml ) None 420 + 26 HRP - conjugated anti -mouse IgG and an AP -conjugated LPS (1 ug/ ml ) Acetaminophen ( 5 UM ) 275 anti - rabbit IgG were added to the wells . Following another LPS ( 1 ug /ml ) Aspirin (5 uM ) 240 17 incubation and set of washes , the HRP - and AP - fluorogenic LPS ( 1 ug /ml ) Ibuprofen ( 5 uM ) ) 253 = 32 substrates were added . Finally , a Victor V multilabel plate LPS ( 1 ug /ml ) Naproxen ( 5 uM ) 284 11 LPS ( 1 ug /ml ) Acetaminophen ( 50 uM ) 243 15 reader ( PerkinElmer ) was used to read the fluorescence LPS ( 1 ug /ml ) Aspirin (50 UM ) 258 + 21 emitted at 600 nm (COX2 fluorescence ) and 450 nm LPS (1 ug/ ml ) Ibuprofen (50 UM ) 266 19 (GAPDH fluorescence ) . Results are expressed as relative LPS ( 1 ug/ ml ) Naproxen (50 UM ) 279 + 23 levels of total COX2 as determined by relative fluorescence unit (RFUS ) and normalized to the housekeeping protein GAPDH . Analgesics Inhibit PGE2 Responses ofMouse Bladder Cells Analysis of PGE2 Responses to an Inflammatory Stimulus [ 0245 ] Prostaglandin E2 responses were analyzed by a [0249 ] The secretion of PGE2 in culture supernatants of sequential competitive ELISA ( R & D Systems) . More spe mouse bladder cells was measured to determine the biologi cifically , culture supernatants or PGE2 standardswere added cal significance of the alteration of mouse bladder cell to the wells of a 96 -well polystyrene microplate coated with COX2 levels by analgesics . As shown in Table 5 , PGE2 was a goat anti- mouse polyclonal antibody . After one hour not detected in the culture supernatants of unstimulated incubation on a microplate shaker, an HRP - conjugated bladder cells or bladder cells cultured in the presence of PGE2 was added and plates incubated for an additional two carbachol. Consistent with COX2 responses described hours at room temperature. The plates were then washed and above, stimulation of mouse bladder cells with LPS induced HRP substrate solution added to each well . The color was the secretion of high levels of PGE2 . Addition of the allowed to develop for 30 min and the reaction stopped by analgesics acetaminophen , aspirin , ibuprofen and naproxen addition sulfuric acid before reading the plate at 450 nm with suppressed the effect of LPS on PGE2 secretion and no wavelength correction at 570 nm . Results are expressed as difference was seen between the responses of cells treated mean pg /ml of PGE2 . with the 5 or 50 UM dose of analgesic . Other Assays TABLE 5 [ 0246 ] The release of PGH2, PGE, Prostacydin , Throm boxane , IL - 1B , IL - 6 , and TNF - a , the production of CAMP PGE2 secretion by mouse bladder cells after in and cGMP, the production of IL - 1B , IL -6 , TNF - a and COX2 vitro stimulation and treatment with analgesic . mRNA, and surface expression of CD80 , CD86 and MHC PGE2 levels class II molecules are determined as described in Example Stimuli Analgesic (pg / ml ) None None < 20 . 5 Carbachol (MM ) None < 20 . 5 Results LPS ( 1 ug /ml ) None 925 + 55 LPS ( 1 ug/ ml ) Acetaminophen ( 5 UM ) 619 = 32 Analgesics Inhibit COX2 Responses of Mouse Bladder LPS ( 1 ug /ml ) Aspirin ( 5 UM ) 588 = 21 LPS ( 1 ug/ ml ) Ibuprofen ( 5 uM ) ) 593 + 46 Cells to an Inflammatory Stimulus LPS ( 1 ug /ml ) Naproxen ( 5 UM ) 597 + 19 LPS ( 1 ug/ ml ) Acetaminophen (50 uM ) 600 + 45 [ 0247 ] Several analgesics ( acetaminophen , aspirin , ibu LPS ( 1 ug/ ml ) Aspirin (50 UM ) 571 53 profen and naproxen ) were tested on mouse bladder cells at LPS ( 1 ug /ml ) Ibuprofen (50 UM ) 568 + 32 the concentration of 5 uM or 50 uM to determine whether LPS ( 1 ug /ml ) Naproxen (50 uM ) 588 + 37 the analgesics could induce COX2 responses. Analysis of 24 - hour cultures showed that none of the analgesics tested induced COX2 responses in mouse bladder cells in vitro . [0250 ] In summary, these data show that the analgesics [0248 ] The effect of these analgesics on the COX2 alone at 5 uM or 50 uM do not induce COX2 and PGE2 responses of mouse bladder cells to carbachol or LPS responses in mouse bladder cells. The analgesics at 5 uM or stimulation in vitro was also tested . As indicated in Table 1 , 50 UM , however , significantly inhibit COX2 and PGE2 the dose of carbachol tested has no significant effect on responses of mouse bladder cells stimulated in vitro with COX2 levels in mouse bladder cells . On the other hand , LPS LPS ( 1 ug /ml ) . No significant effect of analgesics was significantly increased total COX2 levels . Interestingly , observed on COX2 and PGE2 responses of mouse bladder acetaminophen , aspirin , ibuprofen and naproxen could all cells stimulated with carbachol ( 1 mM ). US 2018 /0264013 A1 Sep . 20 , 2018 24

Example 4 : Effect of Analgesic Agents , Botulinum frequency ( and volume) of urination are evaluated . Bladder Neurotoxin and Antimuscarinic Agents on Mouse outputs are determined by monitoring water intake and cage Bladder Smooth Muscle Cell Contraction litter weight. Serum PGH2, PGE , PGE2, Prostacydin , Thromboxane , IL - 6 , TNF - a , CAMP, and cGMP levels are Experimental Design determined by ELISA . CD80 , CD86 , MHC class II expres [0251 ] Cultured mouse or rat bladder smooth muscle cells sion in whole blood cells are determined by flow cytometry . and mouse or rat bladder smooth muscle tissue are exposed [0268 ] At the end of the experiment, animals are eutha to inflammatory stimuli and non - inflammatory stimuli in the nized and ex vivo bladder contractions are recorded with a presence of analgesic agent and / or antimuscarinic agent at Grass polygraph . Portions of bladders are fixed in formalin , various concentrations . The stimuli - induced muscle contrac and COX2 responses are analyzed by immunohistochemis tion is measured to evaluate the inhibitory effect of the try. analgesic agent and/ or antimuscarinic agent. ( 0252 ) The effectors , analgesic agents and antimuscarinic Example 6 : Effect of Analgesic Agents , Botulinum agents are described in Example 2 . Neurotoxin and Antimuscarinic Agents on Human [ 0253] Primary culture of mouse bladder smooth muscle Bladder Smooth Muscle Cell Responses to cells are subjected to short term ( 1 - 2 hrs ) or long term ( 24 - 48 Inflammatory and Non - Inflammatory Stimuli hrs ) stimulation of with : [0254 ) ( 1 ) Each analgesic agent alone at various doses . Experimental Design [0255 ] ( 2 ) Each analgesic agent at various doses in the [0269 ] This study is designed to characterize how the presence of LPS . optimal doses of analgesic determined in Examples 1 - 5 [ 0256 ) ( 3 ) Each analgesic agent at various doses in the affect human bladder smooth muscle cells in cell culture or presence of carbachol or acetylcholine. tissue cultures, and to address whether different classes of [0257 ) ( 4 ) Each analgesic agent at various doses in the analgesics can synergize to more efficiently inhibit COX2 presence of AA , DGLA , or EPA . and PGE2 responses . [0258 ] ( 5 ) Botulinum neurotoxin A alone at various doses . (0270 ] The effectors , analgesic agents and antimuscarinic [ 0259) . ( 6 ) Botulinum neurotoxin A at various doses in the agents are described in Example 2 . presence of LPS . [0271 ] Human bladder smooth muscle cells are subjected [ 0260 ) ( 7 ) Botulinum neurotoxin A at various doses in the to short term ( 1 - 2 hrs ) or long term ( 24 - 48 hrs ) stimulation presence of carbachol or acetylcholine . of with : 0261] ( 8 ) Botulinum neurotoxin A at various doses in the [0272 ] ( 1 ) Each analgesic agent alone at various doses. presence of AA , DGLA , or EPA . [0273 ] ( 2 ) Each analgesic agent at various doses in the [ 0262] ( 9 ) Each antimuscarinic agent alone at various presence of LPS . doses . (0274 ) ( 3 ) Each analgesic agent at various doses in the [ 0263) ( 10 ) Each antimuscarinic agent at various doses in presence of carbachol or acetylcholine . the presence of LPS . 102751 ( 4 ) Each analgesic agent at various doses in the [ 0264 ] ( 11 ) Each antimuscarinic agent at various doses in presence of AA , DGLA , or EPA . the presence of carbachol or acetylcholine . 0276 ) ( 5 ) Botulinum neurotoxin A alone at various doses . [0277 ] (6 ) Botulinum neurotoxin A at various doses in the [ 0265 ] ( 12 ) Each antimuscarinic agent at various doses in presence of LPS . the presence of AA , DGLA , or EPA . [0278 ] (7 ) Botulinum neurotoxin A at various doses in the Materials and Methods presence of carbachol or acetylcholine . [ 0279 ] ( 8 ) Botulinum neurotoxin A at various doses in the [0266 ] Primary mouse bladder cells are isolated as presence of AA , DGLA , or EPA . described in Example 3 . In selected experiments , cultures of [0280 ] ( 9 ) Each antimuscarinic agent alone at various bladder tissue are used . Bladder smooth muscle cell con doses . tractions are recorded with a Grass polygraph ( Quincy Mass , [0281 ] ( 10 ) Each antimuscarinic agent at various doses in USA ). the presence of LPS . 10282 ) ( 11 ) Each antimuscarinic agent at various doses in Example 5 : Effect of Oral Analgesic Agents and the presence of carbachol or acetylcholine . Antimuscarinic Agents on COX2 and PGE2 (0283 ] ( 12 ) Each antimuscarinic agent at various doses in Responses of Mouse Bladder Smooth Muscle Cells the presence of AA , DGLA , or EPA . The cells are then analyzed for the release of PGH , , PGE , PGE , , Prostacydin , Experimental Design : Thromboxane , IL - 1B , IL - 6 , TNF - a , the COX2 activity, the [ 0267] Normal mice and mice with over active bladder production of CAMP and CGMP, the production of IL - 1B , syndrome are given oral doses of aspirin , naproxen sodium , IL - 6 , TNF - a and COX2 mRNA , and surface expression of ibuprofen , Indocin , nabumetone, Tylenol ( acetaminophen ) , CD80 , CD86 and MHC class II molecules . Celecoxib , oxybutynin , solifenacin , darifenacin , atropine and combinations thereof. Control groups include untreated Example 7 : Effect of Analgesic Agents , Botulinum normal mice and untreated OAB mice without over active Neurotoxin and Antimuscarinic Agents on Human bladder syndrome. Thirty (30 ) min after last doses, the Bladder Smooth Muscle Cell Contraction bladders are collected and stimulated ex vivo with carbachol or acetylcholine. In selected experiments , the bladders are Experimental Design treated with botulinum neurotoxin A before stimulation with [0284 ] Cultured human bladder smooth muscle cells are carbachol. Animals are maintained in metabolic cages and exposed to inflammatory stimuli and non -inflammatory US 2018 /0264013 A1 Sep . 20 , 2018 25 stimuli in the presence of analgesic agent and /or antimus [0302 ] After 24 hours of culture , 150 ul of culture super carinic agent at various concentrations . The stimuli - induced natants were collected , spun down for 2 min at 8 , 000 rpm at muscle contraction is measured to evaluate the inhibitory 4° C . to remove cells and debris and stored at - 70° C . for effect of the analgesic agent and /or antimuscarinic agent. analysis of Prostaglandin E2 (PGE ) responses by ELISA . [ 0285 ) The effectors , analgesic agents and antimuscarinic Cells were fixed , permeabilized and blocked for detection of agents are described in Example 2 . COX2 using a fluorogenic substrate . In selected experiment [ 0286 ] Human bladder smooth muscle cells are subjected cells were stimulated 12 hours in vitro for analysis of COX2, to short term ( 1 - 2 hrs ) or long term ( 24 - 48 hrs ) stimulation PGE2 and cytokine responses. of with : [ 0287 ] ( 1 ) Each analgesic agent alone at various doses . Analysis of COX2 , PGE2 and Cytokine Responses [ 0288 ] ( 2 ) Each analgesic agent at various doses in the [0303 ] COX2 and PGE2 responses were analyzed as presence of LPS . described in Example 3 . Cytokine responses were analyzed (0289 ) ( 3 ) Each analgesic agent at various doses in the as described in Example 2 presence of carbachol or acetylcholine . [0304 ] Results [ 0290 ) ( 4 ) Each analgesic agent at various doses in the [0305 ) Analgesics Inhibit COX2 Responses of Normal presence of AA , DGLA , or EPA . Human Bladder Smooth Muscle Cells to Inflammatory and [ 0291 ] ( 5 ) Botulinum neurotoxin A alone at various doses. [ 0292 ] ( 6 ) Botulinum neurotoxin A at various doses in the Non - Inflammatory Stimuli presence of LPS . [0306 ] Analysis of cells and culture supernatants after 24 (0293 ) ( 7 ) Botulinum neurotoxin A at various doses in the hours of cultures showed that none of the analgesics tested presence of carbachol or acetylcholine . alone induced COX2 responses in normal human bladder 10294 ( 8 ) Botulinum neurotoxin A at various doses in the smooth muscle cells . However , as summarized in Table 6 , presence of AA , DGLA , or EPA . carbachol induced low , but significant COX2 responses in [ 0295 ] (9 ) Each antimuscarinic agent alone at various normal human bladder smooth muscle cells . On the other doses . hand , LPS treatment resulted in higher levels of COX2 [0296 ] ( 10 ) Each antimuscarinic agent at various doses in responses in normal human bladder smooth muscle cells . the presence of LPS . Acetaminophen , aspirin , ibuprofen and naproxen could all [ 02971 ( 11 ) Each antimuscarinic agent at various doses in suppress the effect of carbachol and LPS on COX2 levels . the presence of carbachol or acetylcholine . The suppressive effect of the analgesics was seen on LPS [ 0298 ] ( 12 ) Each antimuscarinic agent at various doses in induced responses when these drugs were tested at either 5 the presence of AA , DGLA , or EPA . Bladder smooth muscle UM or cell contractions are recorded with a Grass polygraph ( Quincy Mass, USA ) . TABLE 6 COX2 expression by normal human bladder smooth muscle Example 8 : Effect of Analgesic Agents on Normal cells after in vitro stimulation with inflammatory and Human Bladder Smooth Muscle Cell Responses to non - inflammatory stimuli and treatment with analgesic Inflammatory and Non - Inflammatory Signals Total COX2 Total COX2 levels levels Experimental Design (Normalized (Normalized RFUS ) RFUS) Culture of Normal Human Bladder Smooth Muscle Cells Stimuli Analgesic subject 1 subject 2 None None 230 199 [0299 ] Normal human bladder smooth muscle cells were Carbachol 10 -3M Acetaminophen (50 UM ) 437 462 isolated by enzymatic digestion from macroscopically nor Carbachol 10 - 3 M Aspirin (50 uM ) 298 310 mal pieces of human bladder . Cells were expended in vitro Carbachol 10 - 3 M Ibuprofen ( 50 MM ) 312 297 by culture at 37° C . in a 5 % CO , atmosphere in RPMI 1640 Carbachol 10 - 3 M Naproxen ( 50 UM ) 309 330 Carbachol 10 -3M Acetaminophen (50 UM ) 296 354 supplemented with 10 % fetal bovine serum , 15 mM HEPES , LPS ( 10 ug/ ml ) None 672 633 2 mM L - glutamine , 100 U /ml penicillin , and 100 mg/ml of LPS ( 10 ug /ml ) Acetaminophen ( 5 UM ) 428 457 streptomycin and passage once a week by treatment with LPS ( 10 ug/ ml ) Aspirin ( 5 UM ) 472 491 trypsin to detach cells followed by reseeding in a new LPS ( 10 ug /ml ) Ibuprofen ( 5 uM ) 417 456 LPS ( 10 ug/ ml ) Naproxen (5 uM 458 501 culture flask . The first week of culture, the culture medium LPS (10 ug /ml ) Acetaminophen (50 UM ) 399 509 was supplemented with 0 . 5 ng /ml epidermal growth factor , LPS ( 10 ug /ml ) Aspirin (50 uM ) 413 484 2 ng/ ml fibroblast growth factor, and 5 ug/ ml insulin . LPS ( 10 ug /ml ) Ibuprofen ( 50 UM ) 427 466 [0300 ] Treatment of normal human bladder smooth LPS ( 10 ug /ml ) Naproxen ( 50 UM ) 409 458 muscle cells with analgesics in vitro # Data are expressed as mean of duplicates [ 0301] Bladder smooth muscle cells trypsinized and seeded in microculture plates at a cell density of 3x104 cells 103071 Analgesics Inhibit PGE2 Responses of Normal per well in 100 ul were treated with analgesic solutions ( 50 Human Bladder Smooth Muscle Cells to Inflammatory and ul/ well ) either alone or together carbachol (10 -Molar , 50 Non - Inflammatory Stimuli ul/ well ) , as an example of non - inflammatory stimuli, or 10308 ]. Consistent with the induction of COX2 responses lipopolysaccharide (LPS ) of Salmonella typhimurium 1 described above , both carbachol and LPS induced produc ug/ ml , 50 ul/ well ), as an example of non - inflammatory tion of PGE2 by normal human bladder smooth muscle cells . stimuli. When no other effectors were added to the cells , 50 Acetaminophen , aspirin , ibuprofen and naproxen were also ul of RPMI 1640 without fetal bovine serum were added to found to suppress the LPS - induced PGE2 responses at either the wells to adjust the final volume to 200 ul. 5 uM or 50 uM ( Table 7 ) . US 2018 /0264013 A1 Sep . 20 , 2018 26

TABLE 7 TABLE 9 PGE2 secretion by normal human bladder smooth muscle cells IL - 6 secretion by normal human bladder smooth muscle cells after in vitro stimulation with inflammatory and non after in vitro stimulation with inflammatory and non inflammatory stimuli and treatment with analgesic . inflammatory stimuli and treatment with analgesic IL - 6 IL - 6 PGE2 levels# PGE2 levels (pg / ml ) * (pg /ml ) (pg /ml ) (pg / ml ) Stimuli Analgesic Stimuli Analgesic Subject 1 Subject 2 Subject 1 Subject 2 None None < 5 < 5 None None < 20 . 5 < 20 . 5 Carbachol 10 - 3 M None 232 278 Carbachol 10 -3M Acetaminophen (50 uM ) 129 104 Carbachol 10 - 3 M Acetaminophen (50 UM ) 119 135 Carbachol 10 - 3 M Aspirin (50 UM ) 76 62 Carbachol 10 -3M Aspirin (50 UM ) 95 146 Carbachol 10 - 3 M Ibuprofen (50 MM ) 89 59 Carbachol 10 -3M . Ibuprofen (50 uM ) 107 118 Carbachol 10 - 3 M Naproxen (50 uM ) 84 Carbachol 10 - 3 M Naproxen (50 uM ) 114 127 Carbachol 10 -3M Acetaminophen (50 uM ) 77 LPS ( 10 ug/ml ) None 4838 4383 LPS ( 10 ug/ ml ) None 1125 998 LPS ( 10 ug/ ml ) Acetaminophen ( 5 UM ) 2012 2308 LPS ( 10 ug/ ml ) Acetaminophen (5 uM ) 817 542 LPS ( 10 ug /ml ) Aspirin ( 5 uM ) 2199 2089 LPS ( 10 ug /ml ) Aspirin ( 5 uM ) 838 598 LPS ( 10 ug /ml ) Ibuprofen ( 5 UM ) 2063 2173 LPS ( 10 ug /ml ) Ibuprofen ( 5 uM ) 824 527 LPS (10 ug /ml ) Naproxen ( 5 UM 2077 2229 LPS ( 10 ug /ml ) Naproxen ( 5 uM 859 506 LPS ( 10 ug/ ml ) Acetaminophen ( 50 uM ) 2018 1983 LPS ( 10 ug /ml ) Acetaminophen (50 UM ) 803 540 LPS (10 ug/ ml ) Aspirin (50 UM ) 1987 2010 812 534 LPS (10 ug /ml ) Ibuprofen (50 UM ) 2021 1991 LPS ( 10 ug/ ml ) Aspirin (50 MM ) Naproxen (50 UM ) 2102 2028 LPS ( 10 ug/ ml ) Ibuprofen (50 M ) 821 501 LPS ( 10 ug /ml ) LPS ( 10 ug /ml ) Naproxen (50 UM ) 819 523 # Data are expressed as mean of duplicates * Data are expressed as mean of duplicates [0311 ] Primary normal human bladder smooth muscle cells were isolated , cultured and evaluated for their [0309 ] Analgesics Inhibit Cytokine Responses of Normal responses to analgesics in the presence of non - inflammatory Human Bladder Cells to an Inflammatory Stimulus ( carbachol) and inflammatory ( LPS ) stimuli . The goal of this [ 0310 ] Analysis of cells and culture supernatants after 24 study was to determine whether or not normal human hours of cultures showed that none of the analgesics tested bladder smooth muscle cells recapitulate the observations alone induced IL - 6 or TNFa secretion in normal human previously made with murine bladder cells . bladder smooth muscle cells . As shown in Tables 8 and 9 , the [0312 ] The above- described experiment will be repeated doses of carbachol tested induced low , but significant TNFa with analgesic agents and / or antimuscarinic agents in and IL - 6 responses in normal human bladder smooth muscle delayed - release , extended - release , or delayed - and - ex cells . On the other hand , LPS treatment resulted in massive tended - release formulations . induction of these proinflammatory cytokines. Acetamino phen , aspirin , ibuprofen and naproxen suppress the effect of Example 9 carbachol and LPS on TNFa and IL - 6 responses. The [0313 ] Results of an 86 -patient clinical trial showed that a suppressive effect of the analgesics on LPS - induced low dose combination of acetaminophen and ibuprofen in an responses was seen when these drugs were tested at either 5 extended release formulation was effective in reducing uM or 50 uM . nightly bathroom visits . Placebo patients averaged a 9 .8 % improvement, but those using the combination therapy aver TABLE 8 age a 34 . 4 % improvement. More importantly , 38 % of the TNFa secretion by normal human bladder smooth muscle patients averaged a 36 % improvement and an additional cells after in vitro stimulation with inflammatory and 23 % of patients averaged a 65 % improvement. For patients non - inflammatory stimuli and treatment with analgesic ages 61 and older , the double and triple doses of the drug TNFa TNFa were about 50 % more effective than the single dose . This (pg / ml ) # (pg / ml ) differential was hypothesized to be due to the increased Stimuli Analgesic Subject 1 Subject 2 likelihood of arthritis and other pains that might interfere with sleep . Since the drug is very effective in dealing with None None < 5 < 5 Carbachol 10 - 3M None 350 286 those sorts of pains at higher doses, this conclusion seems Carbachol 10 -3M Acetaminophen ( 50 UM ) 138 164 logical. Carbachol 10 - 3 M Aspirin (50 UM ) 110 142 Carbachol 10 - 3 M Ibuprofen (50 UM ) 146 121 [0314 ] The above description is for the purpose of teach Carbachol 10 - 3 M Naproxen (50 UM ) 129 137 ing the person of ordinary skill in the art how to practice the LPS ( 10 ug/ ml ) None 5725 4107 present invention , and it is not intended to detail all those LPS ( 10 ug/ ml ) Acetaminophen ( 5 uM ) 2338 2267 obvious modifications and variations of it which will LPS ( 10 ug /ml ) Aspirin ( 5 UM ) 2479 2187 LPS ( 10 ug/ ml ) Ibuprofen ( 5 uM ) 2733 2288 become apparent to the skilled worker upon reading the LPS ( 10 ug/ ml ) Naproxen ( 5 uM 2591 2215 description . It is intended , however , that all such obvious LPS (10 ug /ml ) Acetaminophen (50 UM ) 2184 2056 modifications and variations be included within the scope of LPS ( 10 ug /ml ) Aspirin (50 UM ) 2266 2089 the present invention , which is defined by the following LPS ( 10 ug /ml ) Ibuprofen (50 uM ) 2603 1997 Naproxen (50 uM ) 2427 2192 claims. The claims are intended to cover the claimed com LPS (10 ug /ml ) ponents and steps in any sequence which is effective to meet # Data are expressed as mean of duplicates. the objectives there intended , unless the context specifically indicates the contrary . US 2018 /0264013 A1 Sep . 20 , 2018 27

What is claimed is : 13 . The method of claim 11 , wherein the one or more 1 . A method for treating a sleep disorder, comprising : analgesics and the anti - insomnia agent are administered administering to a subject in need thereof an effective together. amount of a pharmaceutical composition comprising 14 . The method of claim 11 , wherein the one or more one or more analgesics , analgesics and the anti - insomnia agent are administered wherein the pharmaceutical composition is formulated for separately. immediate - release or controlled -release . 2 . The method of claim 1 , wherein the pharmaceutical 15 . A method for treating insomnia , comprising: composition comprises 5 mg to 2000 mg acetaminophen . administering to a subject in need thereof an effective 3 . The method of claim 1 , wherein the pharmaceutical amount of a pharmaceutical composition comprising 5 composition comprises 50 mg to 1000 mg acetaminophen . mg to 2000 mg acetaminophen and 5 mg to 2000 mg 4 . The method of claim 1 , wherein the pharmaceutical ibuprofen , composition comprises 5 mg to 2000 mg acetaminophen and wherein the acetaminophen and ibuprofen are formulated 5 mg to 2000 mg ibuprofen . for extended - release and wherein the pharmaceutical 5 . The method of claim 1 , wherein the pharmaceutical composition is formulated in the form of an orally composition further comprises an anti - insomnia agent. disintegrating tablet. 6 . The method of claim 1 , wherein the pharmaceutical 16 . A pharmaceutical composition for treating a sleep composition is administered orally . disorder, comprising: 7 . The method of claim 1 , wherein the pharmaceutical one or more analgesics ; composition is administered by transdermal administration . 8 . The method of claim 1 , wherein the one or more one or more anti - insomnia agents ; and analgesics are formulated in an extended -release formula a pharmaceutically acceptable carrier, tion . wherein the one or more anti - insomnia agents comprise 9 . The method of claim 8 , wherein the pharmaceutical melatonin . composition is coated with an enteric coating . 17 . The pharmaceutical composition of claim 16 , wherein 10 . The method of claim 1 , wherein the sleep disorder is the one or more analgesics comprise acetaminophen . insomnia . 18 . The pharmaceutical composition of claim 16 , wherein 11 . The method of claim 10 , further comprising the step the one or more analgesics comprise acetaminophen and an of administering to the subject an effective amount of one or NSAID . more active agents selected from the group consisting of anti - insomnia agents, antimuscarinic agents , antidiuretic 19 . The pharmaceutical composition of claim 16 , com agents , spasmolytics , a -blockers , 5a - reductase inhibitors , prising 5 mg to 2000 mg acetaminophen and 5 mg to 2000 phosphodiesterase type 5 (PDE5 ) inhibitors and prostaglan mg ibuprofen . din (PD ) pathway inhibitors . 20 . The pharmaceutical composition of claim 19 , com 12 . The method of claim 10 , further comprising the step prising 50 mg to 1000 mg acetaminophen and 50 mg to 1000 of administering to the subject an effective amount of an mg ibuprofen . anti - insomnia agent. * * * *